Intermediates for pharmaceutically useful aminocoumaran derivatives

ABSTRACT

A novel aminocoumaran derivative of the general formula (I): ##STR1## wherein R 1  and R 2  are a hydrogen atom, an acyl group, an alkoxycarbonyl group, an aliphatic group or aromatic group; R 3 , R 4  and R 5  are an optionally acylated hydroxyl optionally substituted amino group, alkoxy group or aliphatic group, or two of R 3 , R 4  and R 5  may be linked together to form a carbocyclic group; R 6  and R 7  are an aliphatic group and at least one of them has a methylene group at the α-position; R 8  and R 9  are a hydrogen atom or an aliphatic group or aromatic group, or a salt thereof is useful for medicines for preventing and treating various diseases such as arterial sclerosis, hepatopathy, cerebrovascular diseases and the like.

This application is a division of application Ser. No. 08/305,717, filedSep. 14, 1994 now U.S. Pat. No. 5,478,844 which is a divisional of07/784,988 filed Oct. 30, 1991 now U.S. Pat. No. 5,376,681.

FIELD OF THE INVENTION

The present invention relates to novel aminocoumaran derivatives orsalts thereof and pharmaceutical compositions containing them as anactive component. More specifically, the present invention relates tonovel aminocoumaran derivatives or salts thereof and lipoperoxideformation inhibitory preparations containing them as an activecomponent, which are useful as medicines for preventing and treatingvarious diseases such as arterial sclerosis, hepatopathy,cerebrovascular diseases and the like.

BACKGROUND OF THE INVENTION

As it has become evident that the formation of a lipoperoxide in thebody and a concomitant radical reaction have various harmful effects onthe living body through membrane disorders, enzymatic disorders and thelike, various attempts to use antioxidants and lipoperoxide formationinhibitors as medicines have been made. At present, the mainlipoperoxide formation inhibitors used in the art are derivatives ofnatural antioxidants such as vitamin C, vitamin E and the like, andphenol derivatives (Kenji Fukuzawa, The Japanese Journal of ClinicalMedicine, 46, 2269-2276, 1988). However, their fundamental structuralskeletons are limited and they are not always satisfactory in practicaluse. Thus, it is desired to develop a lipoperoxide formation inhibitorhaving a novel structure that can be effectively and widely utilized inthe medicinal field.

OBJECTS OF THE INVENTION

The main objects of the present invention is to provide novel compoundshaving a lipoperoxide formation inhibitory activity and lipoperoxideformation inhibitory preparations containing them as an activecomponent.

SUMMARY OF THE INVENTION

Under these circumstances, the present inventors synthesized a number ofnovel compounds and tested their antioxidation activity and lipoperoxideformation inhibitory activity, respectively, in order to attain theabove object.

As a result, the inventors have succeeded in creating aminocoumaranderivatives having a novel structure of the general formula (I):##STR2## wherein R¹ and R² are the same or different and are a hydrogenatom, an acyl group, an alkoxycarbonyl group, an optionally substitutedaliphatic or an optionally substituted aromatic group; R³, R⁴ and R⁵ arethe same or different and are an optionally acylated hydroxyl group, anoptionally substituted amino group, an optionally substituted alkoxygroup or an optionally substituted aliphatic group, or two of R³, R⁴ andR⁵ may linked together to form an optionally substituted carbocyclicgroup; R⁶ and R⁷ are the same or different and are an optionallysubstituted aliphatic group, provided that at least one of R⁶ and R⁷ hasmethylene at the α-position; and R⁸ and R⁹ are the same or different andare a hydrogen atom or an optionally substituted aliphatic group or anoptionally substituted aromatic group, or a salt thereof. Further, ithas been found that the novel compounds have activities useful formedicines, for example, strong lipoperoxide formation inhibitoryactivity and the like. Thus, the present invention has been completed.

That is, the present invention provides the novel aminocoumaranderivatives of the general formula (I) or salts thereof and apharmaceutical composition comprising them as an active component.

DETAILED DESCRIPTION OF THE INVENTION

In the general formula (I), the acyl group represented by R¹ and R²includes an acyl group derived from a carboxylic acid and an acyl groupderived from a sulfonic acid and the like. As the acyl group derivedfrom a carboxylic acid, there is a C₁₋₆ acyl group (e.g., formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, etc.). As the acylgroup derived from a sulfonic acid, there is a C₁₋₃ alkylsulfonyl groupsuch as methanesulfonyl, ethanesulfonyl, propanesulfonyl and the likeand phenylsulfonyl group. As the alkoxycarbonyl group represented by R¹and R², there are a lower alkoxycarbonyl group the alkoxy of which has 1to 5 carbon atoms such as methoxycarbonyl group, ethoxycarbonyl groupand the like. The aliphatic group represented by R¹ and R² may be asaturated or unsaturated group and examples thereof include an alkylgroup, an alkenyl group and an alkynyl group. The alkyl group may bestraight, branched or cyclic. Among the alkyl groups, a lower alkylgroup having 1 to 6 carbon atoms is preferred and the examples thereofinclude methyl, ethyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,cyclopropyl, cyclobutyl, cyclopentyl and the like. As the alkenyl grouprepresented by R¹ and R², in general, that having 2 to 6 carbon atoms ispreferred and examples thereof include allyl, propenyl, i-propenyl,2-butenyl, 2,4-butadienyl, 2-pentenyl and the like. As the alkynyl grouprepresented by R¹ and R², in general that having 2 to 6 carbon atoms ispreferred and examples thereof include ethynyl, 2-propynyl and the like.The substituents which these aliphatic groups may have are notespecially limited. As the substituents, any groups which can normallybe used for medicines may be used and examples thereof include hydroxyl,C₁₋₃ alkoxy (e.g., methoxy, ethoxy, n-propoxy or iso-propoxy, etc.),aralkyloxy(phenyl-C₁₋₆ alkyloxy or naphthyl-C₁₋₆ alkyloxy, e.g.,benzyloxy, phenethyloxy, etc.), aryloxy (e.g., phenyloxy, naphthyloxy,pyridyloxy, imidazolyloxy, etc.), mercapto, C₁₋₃ alkylthio (e.g.,methylthio or ethylthio, etc.), C₁₋₃ alkylsulfonyl (e.g., methylsulfonylor ethylsulfonyl, etc.), C₁₋₃ alkylsulfinyl (e.g., methylsulfinyl orethylsulfinyl, etc.), aralkylthio(phenyl-C₁₋₆ alkylthio or naphthyl-C₁₋₆alkylthio, e.g., benzylthio, phenethylthio, etc.),aralkylsulfonyl(phenyl-C₁₋₆ alkylsulfonyl or naphthyl-C₁₋₆alkylsulfonyl, e.g., benzylsulfonyl, phenethylsulfonyl, etc.),aralkylsulfinyl(phenyl-C₁₋₆ alkylsulfinyl or naphthyl-C₁₋₆alkylsulfinyl, e.g., benzylsulfinyl, phenethylsulfinyl, etc.), arylthio(e.g., phenylthio, naphthylthio, pyridylthio, imidazolylthio, etc.),arylsulfonyl (e.g., phenylsulfonyl, naphthylsulfonyl, pyridylsulfonyl orimidazolylsulfonyl, etc.), arylsulfinyl (e.g., phenylsulfinyl,naphthylsulfinyl, pyridylsulfinyl or imidazolylsulfinyl, etc.), amino,mono- or di-substituted amino which is substituted with 1 or 2 groups ofC₁₋₃ alkyl, aralkyl(phenyl-C₁₋₆ alkyl or naphthyl-C₁₋₆ alkyl, etc.) andaryl (phenyl, naphthyl, pyridyl or imidazolyl, etc.) (e.g., methylamino,ethylamino, dimethylamino, benzylamino, phenylamino, pyridylamino,etc.), halogen (e.g., chloro or fluoro), esterified carboxyl [e.g., C₂₋₅alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, etc.)], C₂₋₃ acyl(e.g., acetyl, propionyl, etc.), C₂₋₃ acyloxy (e.g., acetoxy,propionyloxy, etc.), (e.g., acetamido, etc.), C₂₋₅ alkoxycarbonylamino(e.g., methoxycarbonylamino, ethoxycarbonylamino, etc.), a cyclic aminogroup (e.g., pyrrolidino, morpholino, piperazino, etc.), a carboxylgroup, a carbamoyl group and the like. The number of these substituentsis preferably 1 to 2.

As the aromatic group represented by R₁ and R₂, there is a phenyl group.Examples of the substituent on the phenyl group include an amino group,a mono- or di-alkylamino group substituted with a C₁₋₃ lower alkylgroup, halogen, nitro, sulfo, cyano, hydroxyl, carboxyl, C₁₋₅ loweralkyl, C₁₋₃ lower alkoxy, C₂₋₅ acyl, C₁₋₃ lower alkylmercapto and thelike. The number of the substituents is not limited but is preferably 1to 3.

The group represented by --NR¹ R² may substitute the benzene ring of thecoumaran at any position of the ring, preferably at the 5-position ofthe coumaran.

It is preferable that one of R¹ and R² is a hydrogen atom and the otheris a hydrogen atom, a phenyl group or a straight, branched or cyclicC₁₋₆ alkyl group.

When the hydroxyl group represented by R³, R⁴ and R⁵ is acylated, theacyl group includes a C₂₋₅ straight or branched carboxylic acid acylgroup (e.g., acetyl, propionyl, butyryl, isobutyryl, etc.). When theamino group represented by R³, R⁴ and R⁵ has substituents, examples ofthe substituents include those of the optionally substituted aliphaticor aromatic groups represented by R¹ and R². As the alkoxy grouprepresented by R³, R⁴ and R⁵ there is a C₁₋₆ straight or branched alkylgroup or an alkoxy group composed of a cyclic alkyl group. As thesubstituent of the alkoxy group, there are, for example, an amino group,a mono- or di-alkylamino group substituted with a C₁₋₃ lower alkylgroup, halogen, hydroxyl, lower alkoxy, lower alkylmercapto and thelike. Examples of the aliphatic group represented by R³, R⁴ and R⁵ andthe substituents thereof include the groups described with respect tothe aliphatic group represented by R¹ and R². Two of R³, R⁴ and R⁵ maylinked together to form an optionally substituted carbocyclic group and,in this case, a 5- or 6-membered carbocyclic group is preferred.Examples of the substituents thereof include a C₁₋₃ alkyl group, a C₁₋₃alkoxy group, hydroxyl group and the like.

R³, R⁴ and R⁵ are preferably straight, branched or cyclic C₁₋₆ alkylgroups.

Examples of the aliphatic group represented by R⁶ and R⁷ include thegroups described with respect to R¹ and R². The substituent of thealiphatic group represented by R⁶ and R⁷ includes an optionallysubstituted aromatic group in addition to the substituents describedwith respect to the aliphatic group represented by R¹ and R². Theoptionally substituted aromatic groups and the substituent thereofinclude those described with respect to R¹ and R². Further, at least oneof R⁶ and R⁷ has methylene group at the α-position. In other words, R⁶and R⁷ are optionally substituted aliphatic groups and at least one ofthem are a group of the formula --CH₂ R' wherein R' is hydrogen or R'together with --CH₂ form an optionally substituted aliphatic group.Examples of such an aliphatic group and its substituent include thoseexemplified with respect to the groups R⁶ and R⁷.

It is preferable that one of R⁶ and R⁷ is a straight, branched or cyclicC₁₋₆ alkyl group, and the other is a straight, branched or cyclic C₁₋₆alkyl group or aralkyl group (preferably phenyl-C₁₋₆ alkyl ornaphthyl-C₁₋₆ alkyl such as benzyl, phenethyl, pnenylpropyl or the like)which may be substituted with a group having 1 to 5 hetero atoms (N, S,O). Examples of the group having 1 to 5 hetero atoms are C₁₋₃ alkoxy,aralkyloxy, aryloxy, C₁₋₃ alkylthio, C₁₋₃ alkylsuifonyl, C₁₋₃alkylsulfonyl, aralkylthio, aralkylsulfonyl, aralkylsulfinyl, arylthio,arylsulfonyl, arylsulfinyl, mono- or di-substituted amino which issubstituted with 1 or 2 groups of C₁₋₃ alkyl, aralkyl and aryl, andcyclic amino groups.

The aliphatic group represented by R⁸ and R⁹ includes that describedwith respect to R⁶ and R⁷. The aromatic group represented by R⁸ and R⁹includes that described with respect to R¹ and R².

It is preferable that one of R⁸ and R⁹ is a hydrogen atom and the otheris a phenyl group optionally substituted with a hydrogen atom, halogenor a straight, branched or cyclic C₁₋₆ alkyl group, or a straight,branched or cyclic C₁₋₆ alkyl group.

The compound represented by the general formula (I) may have itsstereoisomer depending upon a particular kind of the substituent. Thepresent invention includes not only one isomer but also the mixturethereof.

Salts of the compounds represented by the general formula (I) arepreferably pharmaceutically acceptable salts, and examples of thepharmaceutically acceptable salt include those formed with inorganicacids such as hydrohalogenic acid (e.g., hydrochloric acid, hydrobromicacid, etc.), phosphoric acid, sulfuric acid and the like, and organicacids such as organic carboxylic acids (e.g., oxalic acid, phthalicacid, fumaric acid, maleic acid, etc.), sulfonic acids (e.g.,methanesulfonic acid, benzenesulfonic acid) and the like. Further, whenthe compounds (I) contain acidic groups such as carboxyl group and thelike as the substituents, the salts include inorganic base salts formedwith alkaline metals (e.g., sodium, potassium, etc.) or alkaline earthmetals (e.g., magnesium) and the like and salts formed with organicbases (e.g., amines such as dicyclohexylamine, triethylamine,2,6-lutidine, etc.).

Hereinafter, the compounds of the formula (I) and the salts thereof aresimply referred to as "the compound (I)".

The compound (I) of the present invention can be produced, for example,according to the process of the Scheme-I: ##STR3## wherein R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are as defined above, --CH₂ R' corresponds toR⁶ as defined above and X is a halogen, HSO₄ or NO₃. The residue R'--C═is converted into R⁶ by the above reaction with the compound (III).Namely, R' is a residue which constitutes the residue R⁶ together with--CH₂ --. Examples of the halogen represented by X are chlorine, bromineand the like.

That is, the compound (I) can be produced by cyclizing the compound(II), preferably in the presence of (1) an acid, (2) a halogen molecule,if desired, together with a base, or (3) a peracid, if desired, togetherwith a base. The resulting product is optionally subjected todeprotecting reaction, acylating reaction, hydrogenating reaction,oxidation, carbon chain extension with Wittig reaction or substituentexchanging reaction or a combination of two or more of these reactions.The compound (I) can also be produced by condensation between the phenol(III) and an allyl alcohol derivative, preferably in the presence of asuitable acid catalyst or by reduction of the nitro compound (IV) or thediazo compound (V), and the resulting product can be optionallysubjected to deprotecting reaction, acylating reaction or alkylatingreaction or a combination of two or more of these reactions.

The ring closure reaction by an acid is carried out in an aqueoussolution of a protic acid such as hydrochloric acid, hydrobromic acid orthe like at room temperature to 150° C., or the reaction is carried outin hydrogen chloride gas, boron trifluoride etherate (BF₃.Et₂ O) or thelike in a suitable organic solvent (e.g., chloroform, toluene, etc.),prefarably at a temperature in the range of -5° C. to 150° C.

The ring closure reaction by halogen is carried out by reacting thecompound (II) or a salt thereof with bromine or the like, preferably inan organic solvent such as carbon halide (e.g., chloroform, methylenechloride, etc.), acetic acid or the like, if desired, in the presence ofa base such as sodium acetate, triethylamine or the like at -5° C. to100° C.

The ring closure reaction by a peracid is carried out by using a peracidsuch as m-chloroperbenzoic acid or the like in an organic solvent suchas methylene chloride, if desired, in the presence of a base such astriethylamine at -10° to 50° C.

Friedel-Crafts reaction between the phenol derivative and the allylalcohol derivative is carried out in an organic solvent such asdichloroethane in the presence of sulfuric acid,trifluoromethanesulfonic acid or boron trifluoride etherate, preferablyat a temperature in the range of 0° to 150° C.

The reduction of the nitro compound is carried out by catalytichydrogenation using palladium carbon as a catalyst, by using a metalsuch as iron, zinc, tin or the like in the presence of an acid (e.g.,hydrochloric acid, acetic acid, etc.) or base (e.g., sodium hydroxide,etc.) or by using titanium trichloride in the presence of an acid (e.g.,acetic acid, etc.). The reduction of the diazo compound can be carriedout by similar catalytic hydrogenation or a reducing agent such assodium hydrosulfite in water or an organic solvent at 0° to 100° C.

The oxidation after the above ring closure reaction is carried out byusing the oxidizing agent obtained from dimethyl sulfoxide and oxalylchloride or an oxidizing agent such as chromium trioxide or the like,optionally in the presence of a base such as triethylamine, in anorganic solvent such as acetone at -78° C. to 25° C.

The addition-elimination reaction (Wittig reaction) is carried out usingsodium hydride, sodium hydroxide, sodium alkolate, n-butyllithium,lithium diisopropylamide or the like as a base in a solvent such asdimethylformamide, tetrahydrofuran, dimethoxyethane or the like. Thereaction temperature is preferably -78° C. to 80° C. and the reactiontime is about 0.5 to 24 hours.

In hydrogenation of the double bond, the desired product can be obtainedby using a catalyst such as palladium-carbon according to a conventionalmethod.

The deprotection (hydrolysis) of the protected hydroxyl group can becarried out under conventional conditions of ester hydrolysis. When theproduct is unstable to oxygen under basic conditions, the reaction canbe carried out in an atomosphere of argon to obtain the desiredhydrolysate in high yield.

The acylation can be carried out by using the desired acylating agent(acid anhydride, acid halide or the like), if desired, in the presenceof a base catalyst (preferably, sodium hydride, potassium carbonate,pyridine, triethylamine or the like) or an acid catalyst (e.g., sulfuricacid, hydrochloric acid or the like) in an organic solvent (e.g.,dimethylformamide, acetone, tetrahydrofuran). The reaction temperatureis about -10° C. to 100° C. and the reaction time is about 10 minutes to15 hours.

For carrying out the substituent exchanging reaction, for example, a2-halomethyl-2,3-dihydrobenzofuran derivative cyclized by a halogen isreacted with an amine, thiol, alcohol or the like without using anysolvent or in an organic solvent such as dimethylformamide, toluene orthe like, if desired, in the presence of a base (e.g., sodium hydride,etc.) at a temperature in the range of -5° C. to 200° C. If desired, anautoclave is used as a reactor.

Examples of the alkylating reaction include alkylation of an amino groupor a hydroxyl group and the like. For the alkylation, there can be useda halogenated alkyl (examples of the halogen are chlorine, bromine andiodine), alkyl esters of sulfuric acid or sulfonic acid, alkyl esters ofphosphorous acid and the like. Normally, the alkylating agent is used inequal or twice amount and the reaction is carried out in the presence ofan inorganic base (e.g., sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, etc.) or an organic base (e.g.,triethylamine, pyridine, etc.). The solvent used in this reaction is notlimited to a specific one and an organic solvent such astetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide or thelike or water can be used. The reaction is normally carried out at atemperature in the range from room temperature to 100° C.

The starting compounds (II), (III), (IV) and (V) can be synthesized by aknown method (e.g., International Publication WO86/05781), a per seknown method or Reference Examples as described hereinafter.

The compound (I) thus obtained can be isolated by conventionalseparation and purification techniques, for example, extraction,chromatography, recrystallization and the like.

When the compound (I) exists as diastereomers, each diastereomer can beoptionally isolated by the above separation and purification techniques.

When the compound (I) is optically active, each of the d-isomer andl-isomer can be separated by the conventional optical resolution.

The compound (I) of the present invention has circulatory systemimprovement activities and antiallergic activities such as improvementof metabolism of poly unsaturated fatty acids (e.g., linolic acid,γ-linolenic acid, α-linolenic acid, arachidonic acid, dihomo-γ-linolenicacid, eicosapentaenoic acid), particularly, inhibitory activity forlipoperoxide formation reaction (antioxidation activity); inhibitoryactivity for formation of 5-lipoxygenase metabolite [e.g., leukotrienes,5-hydroperoxyeicosatetraenoic acid (HPETE), 5-hydroxyeicosatetraenoicacid (HETE), lipoxins, leukotoxines, etc.]; inhibition activity forthromboxane A₂ -synthetase; activity for maintaining and enhancingprostaglandin I₂ -synthetase; LTD₄ receptor antagonism; scavengingactivity for active oxygen species and the like.

Among these activities, the compound (I) of the present inventionparticularly tends to remarkably show lipoperoxide formation inhibitoryactivity (antioxidation activity).

The compound (I) has low toxicity and little side effect.

Accordingly, the compound (I) of the present invention has therapeuticand preventive effects on various diseases of mammal (e.g., mouse, rat,rabbit, dog, monkey, human, etc.) such as thrombosis due to plateletaggregation; ischemic diseases due to constriction of arterial vascularsmooth muscle or vasospasm in the heart, lung, brain and kidney (e.g.,cardiac infarction, cerebral apoplexy, etc.); neuropathy (e.g.,Parkinson's disease, Arzheimer's disease, Lou-Gehring's disease,muscular dystrophy, etc.); functional disorders caused by central damagesuch as cranial injury, spinal injury, etc.; dysmnesia or emotionaldisturbance (disorders accompanied by nerve cell necrosis caused byhypoxia, cerebral lesion, cerebral hemorrhage, cerebral infarction,cerebral thrombosis, etc.); convulsion and epilepsia caused aftercerebral apoplexy, cerebral infarction, cerebral surgery or cranialinjury; nephritis; pulmonary insufficiency; bronchial asthma;inflammation; arterial sclerosis; atherosclerosis; hepatitis; acutehepatitis; cirrhosis; hypersensitivity pneumonitis; immune deficiencysyndrome; circulatory diseases caused by injury of enzymes, tissue,cells, etc. of the living body due to active oxygen species (e.g.,superoxide, hydroxide radical, etc.) (e.g., cardiac infarction, cerebralapoplexy, cerebral edema, nephritis, etc.); tissue fibroplasticphenomenon; carcinogenesis and the like. For example, the compound (I)of the present invention is useful as a medicinal such as anantithrombotic drug, an antivasoconstriction drug, an antiasthmaticdrug, an antiallergic drug, a drug for improving circulatory system suchas the heart and brain, a drug for treating nephritis, a drug fortreating hepatitis, a drug for inhibiting tissue fibroptastic, a drugfor scavenging active oxygen species, a drug for regulating andimproving arachidonate cascade substances and the like.

The compound (I) can be orally or parenterally administered in safely asit is, or in the form of pharmaceutical compositions (e.g., tablets,capsules, solutions, injection preparations, suppositories) combinedwith known pharmaceutically acceptable carriers, excipient and the like.The dose varies depending upon a particular subject, administrationroute, conditions of diseases and the like. For example, in the case ofadministering orally to an adult patient with circulatory diseases, itis advantageous that the compound of the present invention is normallyadministered 1 to 3 times per day with a dose of about 0.1 mg/kg to 20mg/kg body weight, preferably, 0.2 mg/kg to 10 mg/kg body weight.

The following Examples, Reference Examples and Experiments furtherillustrate the present invention in detail but are not to be construedto limit the scope thereof.

EXAMPLE 1 5-Amino-2-benzyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

Sulfuric acid (15 ml) was added to a solution of4-amino-2,3,5-trimethylphenol (20.0 g, 0.13 mol) and2-methyl-3-phenyl-2-propenol (25.0 g, 0.17 mol) in dichloromethane (100ml) and the mixture was heated under reflux for 1 hour. The resultingreaction mixture was neutralized with aqueous saturated sodiumbicarbonate solution and the product was extracted with ethyl acetate.The extract was washed with water and dried and then the solvent wasdistilled off. The residue was purified by silica gel columnchromatography (isopropyl ether) and crystallized from hexane to obtainthe desired compound (7.2 g, yield: 19.3%), m.p. 68°-69° C.

NMR (CDCl₃) δ1.38 (3H, s), 2.06 (3H, s), 2.10 (3H, s), 2.16 (3H, s),2.80 (2H, broad s), 2.85 (2H, d, J=13.6 Hz), 3.08 (2H, d, J=13.6 Hz),7.26 (5H, m).

EXAMPLE 2 5-Amino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuranhydrochloride

4-Amino-2,3,5-trimethylphenol (2.0 g, 13.2 mmol) and 2-methyl-2-propenol(1.15 g, 15.8 g) were heated under reflux in dichloromethane (20 ml)together with sulfuric acid (2 ml) for 18 hours. The reaction mixturewas washed with aqueous saturated sodium bicarbonate solution, dried andthen concentrated. The residue was purified by silica gel columnchromatography (isopropyl ether). The purified product was convertedinto its hydrochloride and it was crystallized from ethanol-isopropylether to obtain the desired compound (460 mg, yield: 14.4%), m.p.248°-250° C.

NMR (DMSO-d₆) δ1.47 (6H, s), 2.08 (3H, s), 2.18 (6H, s), 3.03 (2H, s),9.80 (2H, broad s).

EXAMPLE 3 5-Amino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuranhydrochloride

4-Formylamino2,3,5-trimethyl-1-(2-methyl-2-propenyloxy)benzene (7.33 g,35.7 mmol) was dissolved in methanol (100 ml) and to the solution wasadded conc. hydrochloric acid (30 ml) with ice-cooling. After theatmosphere in the flask was displaced with argon, the mixture was heatedunder reflux for 2 hours. The reaction mixture was cooled, thenneutralized with aqueous sodium bicarbonate solution and extracted withchloroform. The extract was washed with water and then concentratedunder reduced pressure. The residue was crystallized from isopropylether to obtain the desired compound (6.40 g, yield: 99.2%). A part ofthe compound was converted into its hydrochloride and then crystallizedfrom methanol, m.p. 248°-250° C. (dec.).

NMR (DMSO-d₆) δ1.41 (6H, s), 2.02 (3H, s), 2.20 (6H, s), 9.65 (2H, broads).

EXAMPLE 45-Amino-2,2,4,6-tetramethyl-7-(2-methyl-1-propenyl)-2,3-dihydrobenzofuranhydrochloride

According to the same manner as that described above, the title compoundwas synthesized (yield: 80.1%), m.p. 207°-208° C. (dec.).

NMR (DMSO-d₆) δ1.39 (6H, s), 1.46 (3H, s), 1.86 (3H, s), 2.13 (3H, s),2.21 (3H, s), 2.97 (2H, s), 5.90 (1H, s), 9.38 (2H, broad s).

EXAMPLE 55-Acetylamino-2,2,6,7-tetramethyl-4-nitro-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed in Reference Example 48 hereinafter (yield: 89.4%), m.p. 203°C. (dichloromethaneisopropyl ether).

NMR (CDCl₃) δ1.48 (6H, s), 2.15 (3H, s), 2.18 (3H, s), 2.19 (3H, s),3.29 (2H, s), 7.79 (1H, broad s).

EXAMPLE 65-Acetylamino-2,2,4,7-tetramethyl-6-nitro-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 77.6%), m.p. 203°-204° C.(dichloromethane-isopropyl ether).

NMR (CDCl₃) δ1.50 (6H, s), 2.09 (3H, s), 2.12 (3H, s), 2.14 (3H, s),3.00 (2H, s), 7.09 (1H, s).

EXAMPLE 7 7-Amino-2,2,4,5,6-pentamethyl-2,3-dihydrobenzofuranhydrochloride

2,2,4,5,6-Pentamethyl-7-nitro-2,3-dihydrobenzofuran (310 mg, 1.3 mmol)was dissolved in ethanol (10 ml) and the solution was subjected tocatalytic reduction using 5% palladium carbon (0.6 g) as a catalyst.After the catalyst was filtered off, the filtrate was concentrated. Theresidue was purified by column chromatography on silica gel(hexane-isopropyl ether, 7:3), converted into its hydrochloride and thencrystallized from ethanol-isopropyl ether to obtain the desired compound(170 mg, yield: 53.3%), m.p. 207°-212° C.

NMR (DMSO-d₆) δ1.47 (6H, s), 2.08 (3H, s), 2.12 (3H, s), 2.18 (3H, s),3.03 (2H, s), 9.80 (2H, broad s).

EXAMPLE 8 5-Amino-2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydrobenzofuran

2,2,4,6,7-Pentamethyl-5-nitro-3-phenyl-2,3-dihydrobenzofuran (2.0 g, 6.4mmol) was dissolved in ethanol (15 ml) and the solution was subjected tocatalytic reduction using 5% palladium carbon (2.0 g) as a catalyst.After the catalyst was filtered off, the filtrate was concentrated. Theresidue was purified by column chromatography on silica gel (isopropylether) and then crystallized from hexane to obtain the desired compound(1.33 g, yield: 73.6%), m.p. 131°-132° C.

NMR (CDCl₃) δ1.00 (3H, s), 1.48 (3H, s), 1.77 (3H, s), 2.12 (3H, s),2.19 (3H, s), 3.10 (2H, broad s), 4.11 (1H, s), 6.95 (2H, m), 7.20 (3H,m).

EXAMPLE 95-Amino-3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 70.2%), m.p. 126°-127° C. (hexane).

NMR (CDCl₃) δ0.99 (3H, 1.47 (3H, s), 1.77 (3H, s), 2.12 (3H, s), 2.18(3H, s), 3.10 (2H, broad s), 4.09 (1H, s), 6.93 (4H, m).

EXAMPLE 105-Amino-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 85.0%), m.p. 134°-135° C. (hexane).

NMR (CDCl₃) δ1.00 (3H, s), 1.22 (6H, d, J=6.8 Hz), 1.47 (3H, s), 1.78(3H, s), 2.13 (3H, s), 2.19 (3H, s), 2.85 (1H, septet, J=6.8 Hz), 3.10(2H, broad s), 4.08 (1H, s), 6.85 (2H, m), 7.07 (2H, d, J=8.0 Hz).

EXAMPLE 115-Amino-2,2,4,6,7-pentamethyl-3-(3-pyridyl)-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 53.8%), m.p. 130°-131° C. (hexane).

NMR (CDCl₃) δ1.02 (3H, s), 1.50 (3H, s), 1.77 (3H, s), 2.12 (3H, s),2.19 (3H, s), 3.04 (2H, broad s), 4.12 (1H, s), 7.16 (2H, m), 8.36 (1H,m), 8.46 (1H, t, J=3.2 Hz).

EXAMPLE 125-Amino-3-(3-amino-4-dimethylaminophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofurandihydrochloride

The title compound was synthesized as an amorphous product according tothe same manner as that described above (yield: 42.4%).

NMR (DMSO-d₆) δ1.04 (3H, s), 1.44 (3H, s), 1.99 (3H, s), 2.13 (3H, s),2.29 (3H, s), 3.02 (6H, s), 4.24 (1H, s), 6.00-7.50 (5H, m), 9.85 (2H,broad s).

EXAMPLE 135-Amino-3-isopropyl-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 76.6%), m.p. 255°-230° C. (ethanol).

NMR (DMSO-d₆) δ0.70 (3H, d, J=6.6 Hz), 0.96 (3H, d, J=6.6 Hz), 1.21 (3H,s), 1.57 (3H, s), 1.62 (1H, m), 2.09 (3H, s), 2.53 (3H, s), 2.57 (3H,s), 2.76 (1H, d, J=2.8 Hz), 10.07 (2H, broad s).

EXAMPLE 14 4,5-Diamino-2,2,6,7-tetramethyl-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 96.9%), m.p. 248°-251° C. (ethanol).

NMR (DMSO-d₆) δ1.39 (6H, s), 1.93 (3H, s), 2.09 (3H, s), 2.82 (2H, s),3.36 (4H, broad s).

EXAMPLE 155-Acethylamino-6-amino-2,2,4,7-tetramethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 98.7%), m.p. 155°-157° C. (isopropyl ether).

NMR (CDCl₃) δ1.44 (6H, s), 1.82 and 2.23 (3H, s), 2.00-2.05 (6H, m),2.87 (2H, s), 3.75 (2H, broad s), 6.40 and 6.62 (1H, broad s).

EXAMPLE 165-Acethylamino-4-amino-2,2,6,7-tetramethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 91.4%), m.p. 172-173 (ethanol-ether).

NMR (CDCl₃) δ1.46 (6H, s), 1.83 and 2.23 (3H, s), 2.05-2.09 (6H, m),2.83 (2H, s).

EXAMPLE 175-Amino-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydrobenzofuran

2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-5-nitro-2,3-dihydrobenzofuran(1.26 g, 3.9 mmol) was dissolved in methanol (30 ml). Zinc powder (1.3g) and 1N sodium hydroxide (15 ml) were added to the solution and themixture was heated under reflux for 3 hours. Insoluble materials werefiltered off and water was added. The mixture was extracted with ethylacetate. The extract was washed with water, dried and then the solventwas distilled off. The residue was purified by column chromatography onsilica gel (hexane-isopropyl ether, 95:5) and crystallized from hexaneto obtain the desired compound (710 mg, yield: 53.7%), m.p. 119°-120° C.

NMR (CDCl₃) δ1.00 (3H, s), 1.47 (3H, s), 1.78 (3H, s), 2.13 (3H, s),2.20 (3H, s), 2.31 (3H, s), 3.20 (2H, broad s), 4.09 (1H, s), 6.82 (2H,m), 7.10 (2H, m).

EXAMPLE 185-Amino-2,2,4,6,7-pentamethyl-3-(4-propylphenyl)-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 65.6%), m.p. 68°-69° C. (methanol).

NMR (CDCl₃) δ0.90 (3H, t, J=7.2 Hz), 0.99 (3H, s), 1.47 (3H, s), 1.60(2H, sextet, J=7.2 Hz), 1.77 (3H, s), 2.12 (3H, s), 2.19 (3H, s), 2.54(2H, t, J=7.2 Hz), 3.10 (2H, broad s), 4.09 (1H, s), 6.82 (2H, m), 7.03(2H, d, J=8.0 Hz).

EXAMPLE 195-Amino-2,2,4,6,7-pentamethyl-3-(4-pentylphenyl)-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 55.6%), m.p. 67°-68° C. (methanol).

NMR (CDCl₃) δ0.87 (3H, t, J=6.6 Hz), 1.00 (3H, s), 1.31 (4H, m), 1.47(3H, s), 1.58 (2H, m), 1.78 (3H, s), 2.12 (3H, s), 2.19 (3H, s), 2.55(2H, t, J=7.2 Hz), 3.20 (2H, broad s), 4.09 (1H, s), 6.82 (2H, m), 7.03(2H, d, J=8.0 Hz).

EXAMPLE 205-Amino-2,4,6,7-tetramethyl-2-piperidinomethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 82.1%), m.p. 60°-61° C. (isopropyl ether).

NMR (CDCl₃) δ1.30-1.60 (6H, m), 1.42 (3H, s), 2.07 (6H, s), 2.10 (3H,s), 2.35-2.65 (6H, m), 2.80 (1H, d, J=15.9 Hz), 3.10 (2H, broad s), 3.11(1H, d, J=15.9 Hz).

EXAMPLE 215-Amino-2,4,6,7-tetramethyl-2-morpholinomethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 38.0%), m.p. 114°-115° C. (isopropyl ether).

NMR (CDCl₃) δ1.42 (3H, s), 2.07 (9H, s), 2.40-2.70 (6H, m), 2.81 (1H, d,J=15.0 Hz), 3.13 (1H, d, J=15.0 Hz), 3.20 (2H, broad s), 3.67 (4H, t,J=4.6 Hz).

EXAMPLE 225-Amino-2,4,6,7-tetramethyl-2-[2-(dimethylamino)ethyl]-2,3-dihydrobenzofurandihydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 46.5%), m.p. 200°-203° C. (dec.)(ethanol-isopropyl ether).

NMR (DMSO-d₆) δ1.41 (3H, s), 2.06 (3H, s), 2.17 (2H, m), 2.22 (3H, s),2.24 (3H, s), 2.74 (6H, s), 2.96 (1H, d, J=16.0 Hz), 3.11 (2H, m), 3.16(1H, d, J=16.0 Hz), 9.78 (2H, broad s).

EXAMPLE 235-Amino-2,4,6,7-tetramethyl-2-(2-piperidinoethyl)-2,3-dihydrobenzofurandihydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 41.9%), m.p. 260°-270° C. (dec.)(ethanot-isopropyl ether).

NMR (DMSO-d₆) δ1.41 (3H, s), 1.76 (6H, m), 2.06 (3H, s), 2.22 (3H, s),2.23 (3H, s), 2.23 (2H, m), 2.84 (4H, m), 2.95 (1H, d, J=15.8 Hz), 3.05(2H, m), 3.15 (1H, d, J=15.8 Hz), 9.65 (2H, broad s).

EXAMPLE 245-Amino-2,2,4,6-tetramethyl-7-(dimethylamino)methyl-2,3-dihydrobenzofuranoxalate

Aqueous 50% dimethylamine solution (6.46 ml, 64.2 mmol) was addeddropwise to a suspension of paraformaldehyde (1.61 g, 42.8 mmol) inethanol (10 ml). The mixture was stirred at room temperature until themixture became homogeneous (for 30 minutes). This solution was addeddropwise to a solution of4-acethylamino-3,5-dimethyl-2-(2-methyl-2-propenyl)phenol (4.98 g, 21.4mmol) in ethanol (30 ml). The resulting mixture was heated under refluxfor 3.5 hours under an argon atmosphere. The reaction mixture was cooledand then concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel (chloroform-methanol, 95:5) toobtain the desired compound (5.45 g, yield: 87.7%) as brown oil.

This was dissolved in methanol (60 ml) and conc. hydrochloric acid (20ml) was added. The mixture was heated under reflux for 1.5 hours underan argon atmosphere. After the reaction mixture was cooled, excessaqueous sodium bicarbonate solution was added and the mixture wasextracted with chloroform. The extract was washed with water, dried andconcentrated. The residue was purified by column chromatography onsilica gel (chloroform-methanol, 88:12) to obtain the desired compound(4.86 g, yield: 90.5%) as brown oil.

This was dissolved in ethanol (3 ml) and 5N sodium hydroxide was addedto the solution. The mixture was stirred for 13 hours at 200° C. in asealed tube under an argon atmosphere. After the reaction mixture wascooled, water was added and the mixture was extracted with chloroform.The extract was washed with water, dried and then concentrated. Theresidue was purified by column chromatography on silica gel(chloroform-methanol, 88:12) to obtain the product (1.70 g, yield:41.5%). A part of the product was converted into its oxalate salt andthen recrystallized from ethanol to obtain the desired compound, m.p.178°-180° C. (ethanol).

NMR (DMSO-d₆) δ1.39 (6H, s), 2.02 (3H, s), 2.07 (3H, s), 2.74 (6H, s),2.93 (2H, s), 4.13 (2H, s), 4.52 (4H, broad s).

EXAMPLE 255-Amino-2,2,4,6-tetramethyl-7-piperidinomethyl-2,3-dihydrobenzofuranoxalate

The title compound was synthesized according to the same manner as thatdescribed above (yield: 47.9%-41.0%-55.7%), m.p. 110°-112° C. (ethanol).

NMR (DMSO-d₆) δ1.44 (6H, s), 1.62-1.80 (6H, m), 2.01 (3H, s), 2.03 (3H,s), 2.99 (2H, s), 3.11 (4H, broad s), 4.09 (2H, s), 4.48 (4H, broad s).

EXAMPLE 265-Amino-2,2,4,6-tetramethyl-7-morpholinomethyl-2,3-dihydrobenzofuranoxalate

The title compound was synthesized according to the same manner as thatdescribed above (yield: 55.1%-77.3%-55.2%), m.p. 118°-120° C. (ethanol).

NMR (DMSO-d₆) δ1.38 (6H, s), 2.01 (3H, s), 2.08 (3H, s), 2.85 (4H, broads), 2.90 (2H, s), 3.68 (4H, broad s), 3.83 (2H, s), 5.03 (4H, broad s).

EXAMPLE 275-Acetylamino-2-hydroxymethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

4-Acethylamino-2,3,5-trimethyl-6-(2-methyl-2-propenyl) phenol (2.0 g,8.1 mmol) was dissolved in dichloromethane (20 ml). m-Chloroperbezoicacid (70% purity, 2.2 g, 8.9 mmol) was added slowly to the solution withstirring under ice cooling. After the addition was completed, thereaction mixture was stirred at room temperature for 1 hour andtriethylamine (2 ml) was added. The reaction mixture was washed withwater, dried and then concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate) to obtain the desiredcompound (1.1 g, yield: 51.7% yield) as oil.

NMR (CDCl₃) δ1.43 (3H, s), 1.96 (1H, m), 2.07 (3H, s), 2.09 (6H, s),2.20 (3H, s), 2.81 (1H, d, J=15.4 Hz), 3.16 (1H, d, J=15.4 Hz), 3.63(2H, m), 6.66 (1H, broad s).

EXAMPLE 285-Formylamino-2-hydroxymethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 59.9%), m.p. 149°-150° C. (ethylacetate-hexane).

NMR (DMSO-d₆) δ1.33 (3H, s), 1.97 (3H, s), 1.98 (3H, s), 2.00 (3H, s),2.73 (1H, d, J=15.4 Hz), 3.13 (1H, d, J=15.4 Hz), 3.42 (2H, d, J=5.8Hz), 5.01 (1H, t, J=5.8 Hz), 7.83 (0.2H, d, J=11.6 Hz), 8.21 (0.8H, d,J=1.2H), 9.05 (0.2H, d, J=11.6 Hz), 9.20 (0.8H, broad s).

EXAMPLE 292-Bromomethyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

4-Formylamino-2,3,5-trimethyl-6-(2-methyl-2-propenyl)phenol (50 g, 0.21mol) and sodium acetate (30.5 g, 0.37 mol) were added to acetic acid(500 ml). Bromine (16.5 ml, 0.21 mol) was added dropwise to the mixturewith stirring. After the reaction mixture was stirred for 30 minutes,the mixture was poured into ice water and the product was extracted withethyl acetate. The extract was washed with aqueous saturated sodiumbicarbonate solution, dried and then concentrated. The residue wasdissolved in ethyl acetate again and insoluble materials were filteredoff. The filtrate was concentrated and isopropyl ether was added to theresidue. The crystals precipitated were filtered off to obtain thedesired compound (44.0 g, yield: 65.7%), m.p. 157°-158° C.

NMR (CDCl₃) δ1.61 (1.5H, s), 1.63 (1.5H, s), 2.09 (3H, s), 2.11 (3H, s),2.13 (1.5H. s), 2.16 (1.5H, s), 2.93 (1H, d, J=15.8 Hz), 3.28 (0.5H, d,J=15.8 Hz), 3.29 (0.5H, d, J=15.8 Hz), 3.51 (1H, s), 3.53 (1H, s), 6.77(0.5H, broad s), 6.85 (0.5H, d, J=12.0 Hz), 7.96 (0.5H, d, J=12.0 Hz),8.40 (0.5H, d, J=1.4 Hz).

EXAMPLE 305-Acetylamino-2-formyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

A solution of oxalyl chloride (0.45 ml, 4.7 mmol) in dichloromethane (10ml) was cooled to -78° C. and dimethyl sulfoxide (1 ml) was addeddropwise with stirring. After stirring at the same temperature for 2hours, a solution of5-acetylamino-2-hydroxymethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran(1.1 g, 4.2 mmol) in dichloromethane (5 ml) was added dropwise and themixture was stirred for additional 30 minutes. Triethylamine (3.5 ml)was added and the mixture was stirred for 10 minutes. The reactionmixture was washed with 1N hydrochloric acid and aqueous saturatedsodium bicarbonate solution. The reaction mixture was dried and thenconcentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate) to obtain the desired compound (0.47 g,yield: 43.1%) as oil.

NMR (CDCl₃) δ1.55 (3H, s), 2.06 (3H, s), 2.11 (3H, s), 2.13 (3H, s),2.21 (3H, s), 2.94 (1H, d, J=15.8 Hz), 3.41 (1H, d, J=15.8 Hz), 6.72(1H, broad s).

EXAMPLE 312-Formyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 25.5%).

NMR (CDCl₃) δ1.55 (1.5H, s), 1.57 (1,5H, s), 2.08 (3H, s), 2.12 (3H, s),2.15 (3H, s), 2.94 (1H, d, J=15.4 Hz), 3.41 (0.5H, d, J=15.4 Hz) 3.44(0.5H, d, J=15.4 Hz), 7.00 (1H, m), 7.95 (0.5H, d, J=12.0 Hz), 8.34(0.5H, d, J=1.8 Hz), 9.73 (0.5H, s), 9.74 (0.5 Hz, s).

EXAMPLE 32(Z)-5-Acetylamino-2,4,6,7-tetramethyl-2-styryl-2,3-dihydrobenzofuran

A suspension of benzyltriphenylphosphonium chloride (0.7 g, 1.8 mmol) intetrahydrofuran (10 ml) was cooled to -20° C. and n-butyllithium hexanesolution (1.6M, 1.12 ml, 1.8 mmol) was added dropwise. The reactionmixture was stirred for 30 minutes and then a solution of5-acetylamino-2-formyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (0.45g, 1.7 mmol) in tetrahydrofuran (5 ml) was added. The reaction mixturewas stirred at room temperature for additional 30 minutes. Water wasadded to the reaction mixture and the product was extracted with ethylacetate. The extract was washed with water, dried and then concentrated.The residue was purified by column chromatography on silica gel(isopropyl ether-ethyl acetate, 1:1) to obtain the desired compound(0.44 g, yield: 76.2%) as oil.

NMR (CDCl₃) δ1.55 (3H, s), 1.87 (3H, s), 1.98 (3H, s), 2.05 (3H, s),2.19 (3H, s), 2.94 (1H, d, J=15.4 Hz), 3.19 (1H, d, J=15.4 Hz), 5.92(1H, d, J=12.8 Hz), 6.50 (1H, d, J=12.8 Hz), 6.62 (1H, broad s), 7.25(5H, m).

EXAMPLE 33 (Z)-5-Acetylamino-2,4,6,7-tetramethyl-2-[2-(4-fluorophenyl)ethenyl]-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 81.3%).

NMR (CDCl₃) δ1.55 (3H, s), 1.84 (3H, s), 2.00 (3H, s), 2.05 (3H, s),2.19 (3H, s), 2.95 (1H, d, J=14.0 Hz), 3.19 (1H, d, J=14.0 Hz), 5.88(1H, d, J=12.6 Hz), 6.45 (1H, d, J=12.6 Hz), 6.69 (1H, broad s), 7.00(2H, m), 7.26 (2H, m).

EXAMPLE 34 Ethyl3-[5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl]acrylate

2-Formyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (1.0 g,4.1 mmol), triethylphosphono-acetate (0.91 g, 4.1 mmol) and sodiumhydride (60% purity, 162 mg, 4.1 mmol) were added to dimethylformamideand the mixture was stirred at room temperature for 1 hour. The reactionmixture was diluted with water and the product was extracted with ethylacetate. The extract was washed with water and dried and then thesolvent was distilled off. The residue was purified by columnchromatography on silica gel (ethyl acetate-isopropyl ether, 1:1) toobtain the desired compound (0.5 g, yield: 39.0%) as oil.

NMR (CDCl₃) δ1.29 (3H, t, J=7.2 Hz), 1.60 (3H, s), 2.06 (1.5H, s), 2.11(1.5H, s), 2.13 (1.5H, s), 2.15 (1.5H, s), 2.17 (3H, s), 3.05 (1H, d,J=15.4 Hz), 3.15 (1H, d, J=15.4 Hz), 4.19 (2H, d, J=7.2 Hz), 6.02 (1H,d, J=15.6 Hz), 6.92 (0.5H, broad s), 6.95 (0.5H, d, J=12.0 Hz), 7.02(1H, d, J=15.6 Hz), 7.95 (0.5H, d, J=12.0 Hz), 8.39 (0.5H, d, J=1.6 Hz).

EXAMPLE 355-Acethylamino-2,4,6,7-tetramethyl-2-(2-phenylethyl)-2,3-dihydrobenzofuran

5% Palladium carbon (0.3 g) was added to a solution of(Z)-5-acetylamino-2,4,6,7-tetramethyl-2-styryl-2,3-dihydrobenzofuran(1.0 g, 3.0 mmol) in ethanol and the mixture was stirred for 1 hourunder a hydrogen atmosphere. The catalyst was filtered off and then thefiltrate was concentrated. The residue was purified by columnchromatography on silica gel (isopropyl ether-ethyl acetate, 1:1) toobtain the desired compound (0.95 g, yield: 94.4%) as oil.

NMR (CDCl₃) δ1.48 (3H, s), 2.02 (2H, m), 2.05 (3H, s), 2.09 (3H, s),2.14 (3H, s), 2.22 (3H, s), 2.72 (2H, m), 2.89 (1H, d, J=15.4 Hz), 3.05(1H, d, J=15.4 Hz), 7.10-7.30 (5H, m), 7.15 (1H, broad s).

EXAMPLE 36 5-Acetylamino-2-[2-(4-fluorophenyl)ethyl]-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 90.3%).

NMR (CDCl₃) δ1.47 (3H, s), 1.98 (2H, m), 2.06 (3H, s), 2.10 (6H, s),2.20 (3H, s), 2.69 (2H, m), 2.90 (1H, d, J=15.4 Hz), 3.05 (1H, d, J=15.4Hz), 6.70 (1H, broad s), 6.95 (2H, m), 7.13 (2H, m).

EXAMPLE 375-Amino-7-(2-methylpropyl)-2,2,4,6-tetramethyl-2,3-dihydrobenzofuranhydrochloride

10% Palladium carbon (1.0 g) was added to a solution of5-amino-7-(2-methyl-1-propenyl)-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran(1.50 g, 6.11 mmol) in ethanol (100 ml) and the mixture was heated underreflux for 3 hour under a hydrogen atmosphere. The reaction mixture wascooled and filtered and then the filtrate was concentrated. The residuewas crystallized from isopropyl ether to obtain a product (1.45 g,yield: 95.9% yield). This compound was converted into its hydrochloridesalt and then recrystallized from ethanol to obtain the desired compound(0.90 g, yield: 51.9% yield), m.p. 223°-225° C. (ethanol).

NMR (DMSO-d₆) δ0.85 (6H, d, J=6.6 Hz), 1.39 (6H, s), 1.63-1.84 (1H, m),2.21 (3H, s), 2.22 (3H, s), 2.38 (2H, d, J=7.2 Hz), 2.96 (2H, s), 9.54(2H, broad s).

EXAMPLE 38 5-Formylamino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran

5-Amino-2,2,4,6,7- pentamethyl-2,3-dihydrobenzofuran (1.00 g, 4.87 mmol)was dissolved in formic acid (20 ml) and the solution was heated underreflux for 48 hours. The reaction mixture was concentrated under reducedpressure. Saturated sodium bicarbonate solution was added to the residueand the mixture was extracted with chloroform. The extract was washedwith saturated saline, dried and then concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (chloroform-methanol, 97:3) to obtain the desired compound (1.06 g,yield: 93.3%). A part of it was recrystallized fromdichloromethan-isopropyl ether to obtain white prisms, m.p. 177°-179° C.

NMR (CDCl₃) δ1.46 (3H, s), 1.48 (3H, s), 2.09-2.16 (9H, m), 2.94 (2H,s), 6.68 (1H, broad s), 7.97 (0.5H, d, J=12.0 Hz), 8.40 (0.5H, d, J=1.4Hz).

EXAMPLE 39 5-Acetylamino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran

Acetyl chloride (460 mg, 5.84 mmol) was added dropwise with ice coolingto a solution of 5-amino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran(100g, 4.87 mmol) and triethylamine (640 mg, 6.33 mmol) intetrahydrofuran (20 ml). After the addition was completed, the mixturewas stirred for 4 hours. Water was added to the reaction mixture and themixture was extracted with chloroform. The extract was washed withsaturated sodium bicarbonate solution and saturated saline, dried andconcentrated. The residue was purified by column chromatography onsilica gel (chloroform-methanol, 97:3) to obtain the desired compound(920 mg, yield: 76.4%). A part of it was recrystallized fromdichloromethane-isopropyl ether, m.p. 190° C. (dichloromethane-isopropylether).

NMR (CDCl₃) δ1.46 (6H, s), 1.73 and 2.21 (3H, s), 2.06 (3H, s), 2.09(3H, s), 2.14 (3H, s), 2.93 (2H, s), 6.63 (1H, broad s).

EXAMPLE 40 2,2,4,6,7-Pentamethyl-5-propionylamino-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 99.8%), m.p. 146° C. (dichloromethane-isopropylether).

NMR (CDCl₃) δ1.06 and 1.31 (3H, t, J=7.4 Hz), 1.46 and 1.50 (6H, s),1.92 and 2.44 (2H, q, J=7.4 Hz), 2.04-2.13 (9H, m), 2.93 (2H, s), 6.53and 6.59 (1H, broad s).

EXAMPLE 41 5-Butyrylamino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 70.8%), m.p. 136°-138° C.(dichloromethane-isopropylether).

NMR (CDCl₃) δ0.87 and 1.05 (3H, t, J=7.4 Hz), 1.46 and 1.51 (6H, s),1.74-1.92 (2H, m), 2.05-2.09 (9H, m), 2.10-2.12 (2H, m), 2.39 (2H, t,J=7.4 Hz), 2.93 (2H, s), 6.52-6.62 (1H, m), 6.53 and 6.60 (1H, broad s).

EXAMPLE 42 5-Benzoylamino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 84.5%), m.p. 263°-265° C.(dichloromethane-isopropyl ether).

NMR (CDCl₃) δ1.48 (6H, s), 2.12 (6H,s), 2.16 (3H, s), 2.96 (2H, s),7.45-7.57 (3H, m), 7.90-7.96 (2H, m).

EXAMPLE 43 5-Isobutyrylamino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 92.3%), m.p. 170°-172° C.(dichloromethane-isopropyl ether).

NMR (CDCl₃) δ1.30 (6H, d, J=7.0 Hz), 3..46 (6H, s), 2.03 (3H, s), 2.08(6H, s), 2.61 (1H, septet, J=7.0 Hz), 2.92 (2H, s), 6.57 (1H, broad s).

EXAMPLE 445-Ethoxycarbonylamino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 74.6%), m.p. 102°-104° C. (isopropylether-pentane).

NMR (CDCl₃) δ1.31 (3H, t, J=7.4 Hz), 1.45 and 1.46 (6H, s), 2.09 (6H,s), 2.13 (3H, s), 2.93 (2H, s), 4.20 (2H, q, J=7.4 Hz), 5.87 (1H, broads).

EXAMPLE 455-Methanesulfonylamino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 65.7%), m.p. 159°-160° C.(dichloromethane-isopropyl ether).

NMR (CDCl₃) δ1.47 (6H, s), 2.10 (3H, s), 2.25 (3H, s), 2.28 (3H, s),2.93 (2h, s), 3.03 (3H, s), 5.70 (1H, s).

EXAMPLE 462,2,4,6,7-Pentamethyl-5-(p-toluenesulfonylamino)-2,3-dihydrobenzofuran

5-Amino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran (2.00 g, 9.74 mmol)and p-toluenesulfonyl chloride (2.04 g, 10.7 mmol) were dissolved inpyridine (30 ml) and stirred at 50° C. for 1 hour. The reaction mixturewas concentrated under reduced pressure and the residue was dissolved inchloroform. The mixture was washed with in hydrochloric acid andsaturated saline and dried and then the solvent was distilled off underreduced pressure. The residue was purified by column chromatography onsilica gel (hexane-ethyl acetate, 97:3). The crude crystals wererecrystallized from dichloromethane-isopropyl ether to obtain thedesired compound (2.41 g, yield: 68.8% yield), m.p. 219°-220° C.(dichloromethane-isopropyl ether).

NMR (CDCl₃) δ1.46 (6H, s), 1.80 (3H, s), 1.93 (3H, s), 2.01 (3H, s),2.43 (3H, s), 2.87 (2H, s), 5.81 (1H, s), 7.24 (2H, d, J=8.4 Hz), 7.60(2H, d, J=8.4 Hz).

EXAMPLE 47 5-Ethylamino-2-[2-(4-fluorophenyl)ethyl]-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

To tetrahydrofuran (20 ml) were added5-acetylamino-2,4,6,7-tetramethyl-2-[2-(4-fluorophenyl)ethyl]-2,3-dihydrobenzofuran(1.2 g, 3.4 mmol) and lithium aluminum hydride. The mixture was heatedunder reflux for hours. The reaction mixture was poured into ice waterand the product was extracted with ethyl acetate. The extract was washedwith water and dried and then the solvent was distilled off. The residuewas purified by column chromatography on silica gel (isopropylether-ethyl acetate, 2:1) to obtain the desired compound (0.82 g, yield:71.2%) as oil.

NMR (CDCl₃) δ1.21 (3H, t, J=7.2 Hz), 1.47 (3H, s), 1.98 (2H, m), 2.11(3H, s), 2.14 (3H, s), 2.19 (3H, s), 2.70 (2H, m), 2.84 (2H, q, J=7.2Hz), 2.85 (1H, broad s), 2.90 (1H, d, J=14.0 Hz), 3.02 (1H, d, J=14.0Hz), 6.94 (2H, m), 7.12 (2H, m).

EXAMPLE 48 5-Methylamino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuranhydrochloride

Lithium aluminum hydride (2.93 g, 77.2 mmol) was added with ice coolingto a solution of 5-amino-2,2,4,6,7-pentamethyl-2,3-dihydrofuran (9.00 g,38.6 mmol) in tetrahydrofuran (150 ml). The mixture was heated underreflux for 5 hours. After the reaction mixture was cooled, water (4.8ml) was added and the mixture was filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bycolumn chromatography on silica gel (hexane-ethyl acetate, 9:1). Thepurified product was converted into its hydrochloride salt and the saltwas recrystallized from ethanol-ether to obtain the desired compound(4.03 g, yield: 40.8%), m.p. 205°-208° C. (ethanol-ether).

NMR (CDCl₃) δ1.46 (6H, s), 2.08 (3H, s), 2.48 (6H, s), 2.92 (2H, s),2.98-3.02 (3H, m), 10.57 (1H, broad s).

EXAMPLE 49 5-Ethylamino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized as oil according to the same manneras that described above (yield: 34.0%).

NMR (CDCl₃) δ1.45 (6H, s), 1.48 (3H, t, J=8.4 Hz), 2.07 (3H, s), 2.47(3H, s), 2.48 (3H, s), 2.91 (2H, s), 3.35-3.48 (2H, m), 10.53 (1H, broads).

EXAMPLE 50 2,2,4,6,7-Pentamethyl-5-propylamino-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 43.2%), m.p. 185°-187° C. (ethanol-ether).

NMR (CDCl₃) δ0.92 (3H, t, J=7.4 Hz), 1.45 (6H, s), 1.93-2.06 (2H, m),2.07 (3H, s), 2.47 (3H, s), 2.48 (3H, s), 2.91 (2H, s), 3.15-3.29 (2H,m), 10.54 (1H, broad s).

EXAMPLE 51 5-Butyrylamino-2,2,4,6,7-pentamethyl-2,3-dihyrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 39.7%), m.p. 158°-160° C. (ethanol-ether).

NMR (CDCl₃) δ0.86 (3H, t, J=7.4 Hz), 1.23-138 (2H, m), 1.45 (6H, s),1.91-2.06 (2H, m), 2.07 (3H, s), 2.47 (3H, s), 2.49 (2H, s), 3.17-3.32(2H, m), 10.57 (1H. broad s).

EXAMPLE 52 5-Benzylamino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 32.3%), m.p. 155°-157° C. (ethanol-ether).

NMR (CDCl₃) δ1.44 (6H, s), 2.02 (3H, s), 2.10 (3H, m), 2.20 (3H, s),2.82 (2H, s), 4.56 (2H, broad s), 7.19-7.32 (5H, m), 10.89 (1H, broads).

EXAMPLE 532,2,4,6,7-Pentamethyl-5-(2-methylpropyl)amino-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized as oil according to the same manneras that described above (yield: 67.1%).

NMR (CDCl₃) δ1.10 (6H, d, J=6.6 Hz), 1.45 (6H, s), 2.05 (3H, s), 2.44(3H, S), 2.48 (3H, S), 2.54-2.80 (1H, m), 2.90 (2H, s), 2.93-3.04 (2H,m), 10.39 (1H, broad s).

EXAMPLE 545-Acetylamino-4-dimethylamino-2,2,6,7-tetramethyl-2,3-dihydrobenzofuran

Potassium carbonate (4.42 g, 32.0 mmol) and methyl iodide (3.99 ml, 63.9mmol) were added to a solution of5-acetylamino-4-2,2,6,7-tetramethyl-2,3-dihydrobenzofuran (5.30 g, 21.3mmol) in dimethylformamide (100 ml) and the mixture was stirred at roomtemperature for 3 hours. Water was added to the reaction mixture and themixture was extracted with ethyl acetate. The extract was washed withwater and dried and then the solvent was distilled off under reducedpressure. The residue was purified by column chromatography on silicagel (chloroform-methanol, 97:3) and recrystallized fromdichloromethane-isopropyl ether to obtain the desired compound (5.52g,yield: 93.6%), m.p. 186° C.

NMR (CDCl₃) δ1.44 (6H, s), 2.09 (6H, s), 2.21 (3H, s), 2.67 (6H, s),3.09 (2H, s), 7.17 (1H, broad s).

EXAMPLE 555-Acetylamino-2,2,4,7-tetramethyl-6-dimethylamino-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 93.5%), m.p. 142°-143° C. (isopropyl ether).

NMR (CDCl₃) δ1.46 (6H, s), 2.04 (3H, s), 2.10 (3H, s), 2.20 (3H, s),2.78 (6H, s), 2.90 (2H, s), 7.05 (1H, broad s).

EXAMPLE 565-Amino-2,4,6,7-tetramethyl-2-dimethylaminomethyl-2,3-dihydrobenzofuran

Aqueous 50% dimethylamino solution (20 ml) was added to a solution of2-bromomethyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran(4.0 g, 12.8 mmol) in methanol (20 ml) and heated at 160° C. for 15hours in an autoclave. After the reaction mixture was cooled, themixture was diluted with water and the product was extracted with ethylacetate. The extract was washed with water and dried and then thesolvent was distilled off. The residue was purified by columnchromatography on silica gel (chloroform-methanol, 95:5) and thenrecrystallized from isopropyl ether to obtain the desired compound (2.9g, yield: 91.2% yield), m.p. 66°-67° C.

NMR (CDCl₃) δ1.43 (3H, s), 2.07 (6H, s), 2.11 (3H, s), 2.33 (6H, s),2.50 (2H, s), 2.82 (1H, d, J=15.4 Hz), 3.10 (2H, broad s), 3.12 (1H, d,J=15.4 Hz).

EXAMPLE 575-Amino-2,4,6,7-tetramethyl-2-pyrrolidinomethyl-2,3-dihydrobenzofuran

Pyrrolidine (20 ml) was added to2-bromomethyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran(3.0 g, 9.6 mmol) and the mixture was heated at 160° C. in an autoclavefor 15 hours. After the reaction mixture was cooled, the mixture wasdiluted with water and the product was extracted with ethylacetate. Theextract was washed with water and dried and then the solvent wasdistilled off. The residue was purified by column chromatography onsilica gel (chloroform-methanol, 9:1) and recrystallized from hexane toobtain the desired compound (2.2 g, yield: 83.5%), m.p. 85°-86° C.(dec.).

NMR (CDCl₃) δ1.44 (3H, s), 1.72 (4H, m), 2.06 (6H, s), 2.10 (3H, s),2.45-2.65 (4H, m), 2.68 (2H, s), 2.81 (1H, d, J=15,4 Hz), 3.16 (1H, d,J=15.4 Hz), 3.18 (2H, broad s).

EXAMPLE 585-Amino-2,4,6,7-tetramethyl-2-(4-methylpiperazino)-methyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 76.2%), m.p. 76°-77° C. (isopropyl ether).

NMR (CDCl₃) δ1.42 (3H, s), 2.07 (6H, s), 2.09 (3H, s), 2.25 (3H, s),2.40 (4H, m), 2.48 (1H, d, J=14.2 Hz), 2.58 (1H, d, J=14.2 Hz),2.50-2.80 (4H, m), 2.80 (1H, d, J=15.4 Hz), 3.11 (1H, d, J=15.4 Hz),3.25 (2H, broad s).

EXAMPLE 595-Amino-2,4,6,7-tetramethyl-2-[N-(2-piperidinoethyl)aminomethyl]-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 89.2%), m.p. 102°-104° C.(dichloromethane-isopropyl ether).

NMR (DMSO-d₆) δ1.44 (3H, s), 1.50-1.62 (6H, m), 1.73 (3H, broad s), 2.06(3H, s), 2.08 (3H, s), 2.11 (3H, s), 2.36-2.48 (8H, m), 2.75-2.79 (3H,m), 3.13-3.22 (1H, m).

EXAMPLE 605-Amino-2,4,6,7-tetramethyl-2-(N-phenylaminomethyl)-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 35.5%), m.p. 162°-168° C. (ethanol-ether).

NMR (DMSO-d₆) δ1.45 (3H, s), 2.00 (3H, s), 2.20 (3H, s), 2.22 (3H, s),2.90 (1H, d, J=16.4 Hz), 3.22 (1H, d, J=16.4 Hz), 3.31 (2H, s), 6.61(1H, t, J=7.8 Hz), 6.74 (2H, d, J=7.8 Hz), 7.08 (2H, t, J=7.8 Hz), 9.78(3H, broad s).

EXAMPLE 615-Amino-2-(N-benzylaminomethyl)-2,4,6,7-tetramethyl-2,3-dihydrobenzofurandihydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 64.7%), m.p. 228°-232° C. (ethanol-ether).

NMR (DMSO-d₆) δ1.48 (3H, s), 2.07 (3H, s), 2.22 (3H, s), 2.23 (3H, s),2.93 (1H, d, J=16.2 Hz), 3.10 (2H, s), 3.41 (1H, d, J=16.2 Hz), 4.19(2H, s), 7.38-7.42 (3H, m), 7.60-7.65 (2H, m), 9.70 (3H, broad s).

EXAMPLE 625-Amino-2,4,6,7-tetramethyl-2-(N-phenethylamino-methyl)-2,3-dihydrobenzofurandihydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 63.1%), m.p. 178°-181° C. (ethanol).

NMR (DMSO-d₆) δ1.52 (3H, s), 2.08 (3H, s), 2.23 (3H, s), 2.24 (3H, s),2.95-3.50 (8H, s), 7.22-7.38 (5H, m), 9.19 and 9.72 (3H, broad s).

EXAMPLE 635-Amino-2,4,6,7-tetramethyl-2-[N-(4-phenylbutyl)-aminomethyl]-2,3-dihydrobenzofurandihydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 72.6%), m.p. 201°-202° C. (ethanol-ether).

NMR (DMSO-d₆) δ1.50 (3H, s), 1.53-1.74 (4H, m), 2.07 (3H, s), 2.24 (6H,s), 2.59 (2H, t, J=7.0 Hz), 2.91-3.00 (3H, m), 3.22 (2H, s), 3.43 (1H,d, J=15.8 Hz), 7.16-7.29 (5H, m), 9.08 and 9.88 (3H, broad s).

EXAMPLE 645-Amino-2,4,6,7-tetramethyl-2-[N-(3-pyridylmethyl)-aminomethyl]-2,3-dihydrobenzofurantrihydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 54.6%), m.p. 208°-213° C. (ethanol-ether).

NMR (DMSO-d₆) δ1.51 (3H, s), 2.09 (3H, s), 2.23 (6H, s), 2.95 (1H, d,J=16.0 Hz), 3.28 (2H, s), 3.50 (1H, d, J=16.0 Hz), 4.43 (2H, s), 7.97(1H, dd, J=5.4 Hz, 8.0 Hz), 8.74 (1H, d, J=8.0 Hz), 8.88 (1H, d, J=5.4Hz), 9.13 (1H, s), 9.93 (3H, broad s).

EXAMPLE 655-Amino-2-(1-imidazolyl)methyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofurandihydrochloride

Imidazole (10.0 g, 147 mmol) was added to a suspension of2-bromomethyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran(,3.12 g, 10 mmol) in toluene (30 ml) and the mixture was heated at 200°C. in an autoclave for 15 hours. The reaction mixture was washed withwater, dried and the solvent was distilled off. The residue wasdissolved in methanol (30 ml). Aqueous 6N sodium hydroxide solution wasadded to the mixture and the resulting mixture was heated under refluxfor 1 hour. The mixture was diluted with water and the product wasextracted with ethyl acetate. The extract was washed with water, driedand the solvent was distilled off. The residue was purified by columnchromatography on silica gel (chloroform-methanol, 95:5). The purifiedproduct was converted into its hydrochloride salt and thenrecrystallized from ethanol-isopropyl ether to obtain the desiredcompound (1.3 g, yield: 37.8% yield), m.p. 278°-283° C. (dec.).

NMR (DMSO-d₆) δ1.41 (3H, s), 2.08 (3H, s), 2.24 (6H, s), 3.09 (1H, d,J=16.2 Hz), 3.23 (1H, d, J=16.2 Hz), 4.54 (2H, s), 7.66 (1H, d, J=1.6Hz), 7.73 (1H, d, J=1.6 Hz), 9.19 (1H, s), 10.8 (2H, broad s).

EXAMPLE 665-Amino-2,4,6,7-tetramethyl-2-(4-phenylpiperazino)methyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 18.3%), m.p. 94°-95° C. (isopropyl ether).

NMR (CDCl₃) δ1.45 (3H, s), 2.08 (6H, s), 2.12 (3H, s), 2.55-2.90 (8H,m), 2.90-3.50 (6H, m), 6.80-7.00 (3H, m), 7.25 (2H, m).

EXAMPLE 675-Amino-2,4,6,7-tetramethyl-2-(4-phenylpiperidino)methyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 57.5%), m.p. 112°-113° C. (isopropyl ether).

NMR (CDCl₃) δ1.47 (3H, s), 1.75 (4H, m), 2.09 (6H, s), 2.13 (3H, s),2.15-2.50 (4H, m), 2.54 (1H, d, J=14.0 Hz), 2.63 (1H, d, J=14.0 Hz) 2.84(1H, d, J=15.2 Hz), 2.99 (1H, m), 3.15 (1H, d, J=15.2 Hz), 3.19 (2H,broad s), 7.27 (5H, m).

EXAMPLE 68 5-Amino-2,4,6,7-tetramethyl-2-[4-(diphenylmethyl)piperazinomethyl]-2,3-dihydrobenzofuran dihydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 17.7%), m.p. 193°-196° C. (dec.)(ethanol-ether).

NMR (DMSO-d₆) δ1.50 (3H, s), 1.99 (6H, s), 2.21 (3H, s), 3.03-3.51 (12H,m), 5.20 (1H, broad s), 7.33-7.45 (6H, m), 7.68 (4H, broad s).

EXAMPLE 695-Amino-2-benzyloxymethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuranhydrochloride

Benzylalcohol (20 ml) and sodium hydride (60% purity, 1.0 g, 25 mmol)were added to2-bromomethyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran(2.0 g, 6.4 mmol) and the mixture was heated at 180° C. in an autoclavefor 18 hours. After the reaction mixture was cooled, the mixture wasdiluted with water and the product was extracted with ethyl acetate. Theextract was washed with water and dried and then the solvent wasdistilled off. The residue was purified by column chromatography onsilica gel (isopropyl ether). The purified product was converted intoits hydrochloride salt and then recrystallized from ethanol-isopropylether to obtain the desired compound (0.68 g, yield: 30.5%), m.p.195°-200° C.

NMR (DMSO-d₆) δ1.40 (3H, s), 2.05 (3H, s), 2.22 (6H, s), 2.88 (1H, d,J=15.8 Hz), 3.17 (1H, d, J=15.8 Hz), 3.51 (2H, s), 4.56 (2H, s), 7.31(5H, m), 9.71 (2H, broad s).

EXAMPLE 70 5-Amino-2-methoxy-2,4,6,7-tetramethyl-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 49.6%), m.p. 180°-182° C. (ethanol-isopropylether).

NMR (DMSO-d₆) δ1.37 (3H, s), 2.04 (3H, s), 2.22 (6H, s), 2.85 (1H, d,J=16.0 Hz), 3.14 (1H, d, J=16.0 Hz), 3.31 (3H, s), 3.43 (2H, s), 9.77(2H, broad s).

EXAMPLE 715-Amino-2,4,6,7-tetramethyl-2-[2-(dimethylamino)ethoxymethyl]-2,3-dihydrobenzofuran

The title compound was synthesized as an amorphous product according tothe same manner as that described above (yield: 67.8%).

NMR (DMSO-d₆) δ1.40 (3H, s), 2.02 (3H, s), 2.21 (3H, s), 2.23 (3H, s),2.69 (2H, broad s), 2.81-3.44 (12H, m), 9.79 (2H, broad s).

EXAMPLE 725-Formylamino-2,4,6,7-tetramethyl-2-phenylthiomethyl-2,3-dihydrobenzofuran

Sodium hydride (60% purity, 1.0 g, 21.1 mmol) was added to a solution of2-bromomethyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran(6.0 g, 19.2 mmol) and thiophenol in dimethylformamide (50 ml) and themixture was stirred at 80° C. for 1 hour under an argon atmosphere.After the reaction mixture was cooled, the product was extracted withethyl acetate. The extract was washed with water, dried and the solventwas distilled off. The residue was purified by column chromatography onsilica gel (isopropyl ether-ethyl acetate, 1:1) and then the purifiedproduct was recrystallized from ethanol-isopropyl ether to obtain thedesired compound (5.54 g, yield: 83.3% yield), m.p. 130°-131° C.

NMR (CDCl₃) δ1.55 (1.5H, s), 1.56 (1.5H, s), 2.00 (3H, s), 2.06 (1.5H,s), 2.09 (1.5H, s), 2.11 (1.5H, s), 2.14 (1.5H, s), 2.91 (1H, d, J=15.8Hz), 3.23 (0.5H, d, J=15.8 Hz), 3.43 (0.5H, d, J=15.8 Hz), 3.27 (2H, s),6.74 (0.5H, broad s), 6.84 (0.5H, d, J=12.0 Hz), 7.15-7.40 (5H, m), 7.97(0.5H, d, J=12.0 Hz), 8.40 (0.5H, 1.4 Hz).

EXAMPLE 73 2-(4-Fluorophenyl)thiomethyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 95.6%).

NMR (CDCl₃) δ1.53 (1.5H, s), 1.55 (1.5H, s), 2.05 (3H, s), 2.06 (1.5H,s), 2.11 (3H, s), 2.14 (1.5H, s), 2.91 (1H, d, J=15.8 Hz), 3.21 (2H, s),3.22 (0.5H, d, J=15.8 Hz), 3.25 (0.5H, d, J=15.8 Hz), 6.74 (0.5H, broads), 6.82 (0.5H, d, J=12.2 Hz), 6.95 (2H, t, J=9.0 Hz), 7.36 (2H, dd,J=5.2 Hz and 9.0 Hz), 7.97 (0.5H, d, J=12.2 Hz), 8.40 (0.5H, d, J=1.6Hz).

EXAMPLE 745-Formylamino-2-(4-hydroxyphenyl)thiomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 93.1%).

NMR (CDCl₃) δ1.51 (1.5H, s), 1.53 (1.5H, s), 1.99 (1.5H, s), 2.01 (1.5H,s), 2.03 (1.5H, s), 2.07 (1.5H, s), 2.10 (1.5H, s), 2.14 (1.5H, s), 2.84(0.5H, d, J=15.4 Hz), 2.87 (0.5H, d, J=15.8 Hz), 3.10 (0.5H, d, J=15.4Hz), 3.11 (0.5H, d, J=15.8 Hz), 3.20 (0.5H, d, J=15.8 Hz), 3.21 (0.5H,d, J=15.8 Hz), 3.22 (0.5H, d, J=15.4 Hz), 3.23 (0.5H, d, J=15.8 Hz),6.01 (0.5H, broad s), 6.15 (0.5H, broad s), 6.70 (2H, m), 6.81 (0.5H,broad s), 6.85 (1.5H, broad s), 7.25 (2H, m), 7.95 (0.5H, d, J=11.8 Hz),8.39 (0.5H, d, J=1.6 Hz).

EXAMPLE 75 5-Formylamino-2,4,6,7-tetramethyl-2-(1-methyl-2-imidazolyl)thiomethyl-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 88.6%).

NMR (CDCl₃) δ1.53 (1.5H, s), 1.55 (1.5H, s), 1.97 (1.5H, s), 2.03 (1.5H,s), 2.04 (1.5H, s), 2.10 (3H, s), 2.14 (1.5H, s), 2.89 (1H, d, J=15.6Hz), 3.18 (0.5H, d, J=15.6 Hz), 3.24 (0.5H, d, J=15.6 Hz), 3.47 (2H, s),3.49 (1.5H, s), 3.52 (1.5H, s), 6.87 (1H, m), 6.99 (0.5H, d, J=12.0 Hz),7.00 (1H, m), 7.11 (0.5H, broad s), 7.95 (0.5H, d, J=12.0 Hz), 8.37(0.5H, d, J=1.4 Hz).

EXAMPLE 762-(2-Benzothiazolyl)thiomethyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 88.2%), m.p. 190°-192° C. (isopropyl ether).

NMR (CDCl₃) δ1.64 (3H, s), 2.00 (3H, s), 2.07 (1.5H, s), 2.10 (1.5H, s),2.11 (1.5H, s), 2.14 (1.5H, s), 2.99 (1H, d, J=15.8 Hz), 3.27 (0.5H, d,J=15.8 Hz), 3.29 (0.5H, d, J=15.8 Hz), 3.78 (0.5H, d, J=15.4 Hz), 3.79(0.5H, d, J=15.4 Hz), 3.87 (0.5H, d, J=15.4 Hz), 3.88 (0.5H, d, J=15.4Hz), 6.73 (0.5H, broad s), 6.75 (0.5H, d, J=12.0 Hz), 7.20-7.50 (2H, m),7.70-7.85 (2H, m), 7.97 (0.5H, d, J=12.0 Hz), 8.40 (0.5H, d, J=1.6 Hz).

EXAMPLE 775-Formylamino-2,4,6,7-tetramethyl-2-(4-pyridyl)thiomethyl-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 71.6%).

NMR (CDCl₃) δ1.59 (1.5H, s), 1.61 (1.5H, s), 1.97 (3H, s), 2.08 (1.5H,s), 2.10 (1.5H, s), 2.13 (1.5H, s), 2.14 (1.5H, s), 2.98 (1H, d, J=16.0Hz), 3.25 (0.5H, d, J=16.0 Hz), 3.30 (0.5H, d, J=16.0 Hz), 3.31 (2H, s),7.00 (0.5H, d, J=12.0 Hz), 7.05 (0.5H, broad s), 7.17 (2H, dd, J=1.6 Hzand 6.2 Hz), 7.98 (0.5H, d, J=12.0 Hz), 8.36 (2H, dd, J=1.6 Hz and 6.2Hz), 8.37 (0.5H, d, J=1.6 Hz).

EXAMPLE 782-Benzylthiomethyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 83.5%).

NMR (CDCl₃) δ1.49 (1.5H, s), 1.50 (1.5H, s), 2.08 (1.5H, s), 2.12 (6H,s), 2.16 (1.5H, s), 2.71 (1H, d, J=13.4 Hz), 2.77 (1H, d, J=13.4 Hz),2.86 (1H, d, J=15.0 Hz), 3.18 (1H, d, J=15.0 Hz), 3.54 (1H, d, J=13.2Hz), 3.18 (1H, J=13.2 Hz), 6.76 (0.5H, broad s), 6.87 (0.5H, d, J=12.0Hz), 7.30 (5H, m), 7.98 (0.5H, d, J=12.0 Hz), 8.40 (0.5H, d, J=1.4 Hz).

EXAMPLE 795-Formylamino-2,4,6,7-tetramethyl-2-propylthiomethyl-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 93.0%).

NMR (CDCl₃) δ0.96 (3H, t, J=7.4 Hz), 1.52 (1.5H, s), 1.54 (1.5H, s),1.60 (2H, m), 2.08 (3H, s), 2.10 (1.5H, s), 2.12 (1.5H, s), 2.13 (1.5H,s), 2.16 (1.5H, s), 2.58 (2H, dt, J=7.2 Hz and 1.2 Hz), 2.82 (1H, s),2.84 (1H, s), 2.89 (1H, d, J=15.8 Hz), 3.22 (0.5H, d, J=15.8 Hz), 3.24(0.5H, d, J=15.8 Hz), 6.77 (0.5H, broad s), 6.85 (0.5H, d, J=12.0 Hz),7.97 (0.5H, d, J=12.0 Hz), 8.40 (0.5H, d, J=1.6 Hz).

EXAMPLE 805-Formylamino-2-(2-hydroxyethyl)thiomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 57.2%).

NMR (CDCl₃) δ1.52 (1.5H, s), 1.54 (1.5H, s), 2.09 (3H, s), 2.11 (1.5H,s), 2.12 (1.5H, s), 2.13 (1.5H, s), 2.16 (1.5H, s), 2.29 (0.5H, t, J=6.4Hz), 2.35 (0.5H, t, J=6.4 Hz), 2.80 (2H, dt, J=7.2 Hz and 1.2 Hz), 2.87(0.5H, s), 2.89 (1H, s), 2.91 (1H, d, J=15.4 Hz), 3.20 (0.5H, d, J=15.4Hz), 3.22 (0.5H, d, J=15.4 Hz), 3.73 (2H, m), 6.78 (0.5H, broad s), 6.80(0.5H, d, J=12.0 Hz), 7.97 (0.5H, d, J=12.0 Hz), 8.38 (0.5H, d, J=1.4Hz).

EXAMPLE 813-[(5-Formylamino-2,4,6,7-tetramethyl-2,3-dihydro-benzofuran-2-yl)methylthio]propionic acid

The title compound was synthesized as oil according to the same manneras that described above (yield: 94.7%).

NMR (CDCl₃) δ1.52 (1.5H, s), 1.54 (1.5H, s), 2.08 (3H, s), 2.09 (3H, s),2.12 (1.5H, s), 2.14 (1.5H, s), 2.64 (2H, t, J=7.0 Hz), 2.86 (2H, t,J=7.0 Hz), 2.87 (2H, s), 2.90 (1H, d, J=15.4 Hz), 3.22 (1H, d, J=15.4Hz), 6.50 (0.5H, broad s), 6.95 (0.5H, broad s), 7.96 (0.5H, broad s),8.38 (0.5H, d, J=1.6 Hz).

EXAMPLE 82 5-Formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-ylphenylsulfoxide

5-Formylamino-2,4,6,7-tetramethyl-2-phenylthiomethyl-2,3-dihydrobenzofuran(2.3g, 6.7 mmol) was dissolved in methanol (20 ml). Aqueous 1M sodiummetaperiodate solution (20 ml) was added to the solution and the mixturewas stirred for 3 hours. The reaction mixture was diluted with water andthe product was extracted with ethyl acetate. The extract was washedwith water, dried and the solvent was distilled off. The residue wascrystallized from isopropyl ether-ethyl acetate to obtain the desiredcompound (1.54 g, yield: 64.0% yield), m.p. 112°-115° C. (dec.).

NMR (CDCl₃) δ1.62 (3H, s), 2.08 (3H, s), 2.12 (1.5H, s), 2.14 (1.5H, s),2.16 (1.5H, s), 2.18 (1.5H, s), 3.00-3.40 (4H, m), 6.78 (1H, m),7.45-7.70 (5H, m), 7.96 (0.25H, d, J=12.0 Hz), 7.99 (0.25H, d, J=12.0Hz), 8.40 (0.25H, d, J=1.4 Hz), 8.42 (0.25H, d, J=1.4 Hz).

EXAMPLE 83 5-Formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-ylphenylsulfone

5-Formylamino-2,4,6,7-tetramethyl-2-phenylthiomethyl-2,3-dihydrobenzofuran(2.1g, 6.2 mmol) was dissolved in methanol (20 ml). Aqueous 2M sodiummetaperiodate solution (20 ml) was added to the solution and the mixturewas heated under reflux for 3 hours. The reaction mixture was dilutedwith water and the product was extracted with ethyl acetate. The extractwas washed with water, dried and the solvent was distilled off. Theresidue was crystallized from isopropyl ether-ethyl acetate to obtainthe desired compound (1.40 g, yield: 65.9% yield), m.p. 154°-155° C.

NMR (CDCl₃) δ1.70 (1.5H, s), 1.71 (1.5H, s), 1.81 (1.5H, s), 1.84 (1.5H,s), 2.05 (1.5H, s), 2.07 (1.5H, s), 2.12 (1.5H, s), 2.14 (1.5H, s), 3.01(1H, d, J=15.6 Hz), 3.56 (1H, s), 3.58 (1H, s), 3.62 (0.5H, d, J=15.6Hz), 3.67 (0.5H, d, J=15.6 Hz), 6.71 (0.5H, broad s), 6.74 (0.5H, d,J=12.0 Hz), 7.15-7.70 (3H, m), 7.89 (2H, m), 7.96 (0.5H, d, J=t2.0 Hz),8.40 (0.5H, d, J=1.6 Hz).

EXAMPLE 845-Amino-2,4,6,7-tetramethyl-2-(2-phenylethyl)-2,3-dihydrobenzofuran

Aqueous 6N sodium hydroxide solution (3 ml) was added to a solution of5-acetylamino-2,4,6,7-tetramethyl-2-(2-phenylethyl)-2,3-dihydrobenzofuran(0.7 g, 2.1 mmol) in methanol (3 ml) and the mixture was heated at 200°C. in an autoclave for 18 hours. The reaction mixture was diluted withwater and the product was extracted with ethyl acetate. The extract waswashed with water, dried and concentrated. The residue was purified bycolumn chromatography on silica gel (isopropyl ether-ethyl acetate,2:1). The crude crystals were recrystallized from hexane to obtain thedesired compound (0.32 g, yield: 54.5%), m.p. 45°-46° C. (dec).

NMR (CDCl₃) δ1.47 (3H, s), 2.03 (2H, m), 2.07 (3H, s), 2.09 (3H, s),2.14 (3H, s), 2.76 (2H, m), 2.92 (1H, d, J=15.4 Hz), 3.00 (2H, broad s),3.07 (1H, d, J=15.4 Hz), 7.10-7.30 (5H, m).

EXAMPLE 855-Amino-2,4,6,7-tetramethyl-2-[2-(4-fluorophenyl)ethyl]-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 54.6%), m.p. 62°-63° C. (hexane).

NMR (CDCl₃) δ1.47 (3H, s), 1.98 (2H, m), 2.10 (3H, s), 2.14 (3H, s),2.19 (3H, s), 2.72 (2H, m), 2.90 (1H, d, J=14.0 Hz), 3.00 (2H, broad s),3.05 (1H, d, J=14.0 Hz), 6.95 (2H, m), 7.13 (2H, m).

EXAMPLE 86 Methyl3-[5-amino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl]acrylatehydrochloride

3-[5-Acetylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl]acrylicacid ethyl ester (0.5 g, 1.58 mmol) was dissolved in methanol (5 ml).Conc. hydrochloric acid (5 ml) was added to the solution and the mixturewas heated under reflux for 1 hour. The reaction mixture was cooled andthe crystals precipitated were filtered. The crude crystals obtainedwere recrystallized from ethanol-isopropyl ether to obtain the desiredcompound (0.35 g, yield: 74.7% yield), m.p. 225°-234° C. (dec.).

NMR (DMSO-d₆) δ1.58 (3H, s), 2.11 (3H, s), 2.19 (3H, s), 2.21 (3H, s),3.12 (1H, d, J=15.0 Hz), 3.24 (1H, d, J=15.0 Hz), 3.65 (3H, s), 5.93(1H, d, J=16.0 Hz), 7.04 (1H, d, J=16.0 Hz), 9.50 (2H, broad s).

EXAMPLE 875-Amino-2-bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 90.2%), m.p. 235°-245° C. (ethanol-isopropylether).

NMR (DMSO-d₆) δ1.53 (3H, s), 2.04 (3H, s) 2.23 (3H, s), 2.24 (3H, s),3.03 (1H, d, J=16.0 Hz), 3.27 (1H, d, J=16.0 Hz), 3.77 (2H, s), 9.85(2H, broad s).

EXAMPLE 885-Amino-2-phenylthiomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 94.5%), m.p. 130°-131° C. (ethanol-isopropylether).

NMR (DMSO-d₆) δ1.51 (3H, s), 1.87 (3H, s), 2.19 (3H, s), 2.20 (3H, s),2.99 (1H, d, J=15.8 Hz), 3.22 (1H, d, J=15.8 Hz), 3.38 (2H, s),7.10-7.40 (5H, m), 9.69 (2H, broad s).

EXAMPLE 895-Amino-2-(4-fluorophenyl)thiomethyl-2,4,6,7-tetramethyl-2,3-dihydrobanzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above, (yield: 80.9%), m.p. 204°-210° C. (dec.)(ethanol-isopropyl ether).

NMR (DMSO-d₆) δ1.49 (3H, s), 1.84 (3H, s), 2.19 (3H, s), 2.20 (3H, s),2.98 (1H, d, J=15.8 Hz), 3.21 (1H, d, J=15.8 Hz), 3.31 (1H, d, J=14.0Hz), 3.39 (1H, d, J=14.0 Hz), 7.13 (2H, t, J=9.0 Hz), 7.38 (2H, dd,J=9.0 Hz and 5.4 Hz), 9.67 (2H, broad s).

EXAMPLE 905-Amino-2-(4-hydroxyphenyl)thiomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 96.2%), m.p. 230°-236° C. (dec.)(ethanol-isopropyl ether).

NMR (DMSO-d₆) δ1.46 (3H, s), 1.91 (3H, s), 2.18 (6H, s), 2.94 (1H, d,J=15.8 Hz), 3.20 (1H, d, J=15.8 Hz), 3.20 (2H, s), 6.70 (2H, d, J=8.6Hz), 7.19 (2H, d, J=8.6 Hz), 9.45 (2H, broad s), 9.56 (1H, s).

EXAMPLE 915-Amino-2-(1-methylimidazol-2-yl)thiomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofurandihydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 65.3% yield), m.p. 220°-225° C. (dec.)(ethanol-isopropyl ether).

NMR (DMSO-d₆) δ1.50 (3H, s), 1.72 (3H, s), 2.19 (3H, s), 2.24 (3H, s),3.05 (1H, d, J=16.2 Hz), 3.29 (1H, d, J=16.2 Hz), 3.50 (3H, s), 3.56(1H, d, J=14.6 Hz), 3.84 (1H, d, J=14.6 Hz), 7.71 (1H, d, J=1.8 Hz),7.75 (1H, d, J=1.8 Hz), 10.2 (2H, broad s).

EXAMPLE 975-Amino-2-(2-benzothiazolyl)thiomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 89.1%), m.p. 204°-208° C. (dec.)(ethanol-isopropyl ether).

NMR (DMSO-d₆) 6 1.58 (3H, s), 1.76 (3H, s), 2.16 (3H, s), 2.21 (3H, s),3.08 (1H, d, J=15.8 Hz), 3.79 (1H, d, J=14.6 Hz), 3.88 (1H, d, J=14.6Hz), 7.37 (1H, t, J=7.6 Hz), 7.47 (1H, d, J=7.6 Hz), 7.78 (1H, d, J=7.6Hz), 8.01 (1H, d, J=7.6 Hz), 9.65 (2H, broad s).

EXAMPLE 935-Amino-2-benzylthiomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 74.1%), m.p. 170°-172° C. (ethanol-isopropylether).

NMR (DMSO-d₆) δ1.44 (3H, s), 2.07 (3H, s), 2.23 (6H, s), 2.80 (2H, s),2.93 (1H, d, J=16.0 Hz), 3.13 (1H, d, J=16.0 Hz), 3.77 (1H, d, J=13.8Hz), 3.87 (1H, d, J=13.8 Hz), 7.29 (5H, m), 9.77 (2H, broad s).

EXAMPLE 945-Amino-2,4,6,7-tetramethyl-2-(4-pyridyl)thiomethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 80.4%), m.p. 96°-97° C. (ethyl acetate-isopropylether).

NMR (CDCl₃) δ1.58 (3H, s), 2.00 (3H, s), 2.05 (3H, s), 2.06 (3H, s),2.85 (2H, broad s), 2.98 (1H, d, J=15.6 Hz), 3.21 (1H, d, J=15.6 Hz),3.25 (1H, d, J=14.0 Hz), 3.32 (1H, d, J=14.0 Hz), 7.14 (2H, dd, J=4.8 Hzand 2.0 Hz), 8.33 (2H, dd, J=4.8 Hz and 2.0 Hz).

EXAMPLE 955-Amino-2,4,6,7-tetramethyl-2-propylthiomethyl-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 74.6%), m.p. 186°-188° C. (ethanol-isopropylether).

NMR (DMSO-d₆) δ0.97 (3H, t, J=7.4 Hz), 1.40-1.70 (2H, m), 1.53 (3H, s),2.09 (3H, s), 2.50 (6H, s), 2.45-2.60 (2H, m), 2.82 (2H, s), 2.88 (1H,d, J=15.4 Hz), 3.28 (1H, d, J=15.4 Hz), 10.10 (2H, broad s).

EXAMPLE 965-Amino-2-(2-hydroxyethyl)thiomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 32.3%), m.p. 108°-109° C. (ethylacetate-isopropyl ether).

NMR (CDCl₃) δ1.51 (3H, s), 2.07 (3H, s), 2.08 (3H, s), 2.11 (3H, s),2.80 (1H, broad s), 2.81 (2H, t, J=5.4 Hz), 2.82(1H, d, J=15.0 Hz), 2.90(1H, d, J=15.0 Hz), 2.92 (1H, d, J=15.4 Hz), 3.19 (1H, d, J=15.4 Hz),3.20 (2H, broad s), 3.73 (2H, t, J=5.4 Hz).

EXAMPLE 92 3-[(5-Amino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl)methylthio]propionic acid

The title compound was synthesized according to the same manner as thatdescribed above (yield: m.p. 139°-140° C. (ethyl acetate-isopropylether).

NMR (CDCl₃) δ1.51 (3H, s), 2.07 (6H, s), 2.09 (3H, s), 2.64 (2H, t,J=6.8 Hz), 2.80 (1H, d, J=14.0 Hz), 2.87 (1H, d, J=14.0 Hz), 2.88 (2H,t, J=6.8 Hz), 2.91 (1H, d, J=15.4 Hz), 3.20 (1H, d, J=15.4 Hz), 4.90(3H, broad s).

EXAMPLE 98 5-Amino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-ylphenylsulfoxide

The title compound was synthesized as oil according to the same manneras that described above (yield: 21.0%).

NMR (CDCl₃) δ1.60 (1.5H, s), 1.84 (1.5H, s), 2.04 (1.5H, s), 2.09 (4.5H,s), 2.11 (3H, s), 2.90-3.45 (5.5H, m), 3.69 (0.5H, d, J=15.8 Hz), 7.48(3H, m), 7.63 (2H, m).

EXAMPLE 99 5-Amino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-ylphenylsulfone

The title compound was synthesized according to the same manner as thatdescribed above (yield: 91.7% yield), m.p. 150°-151° C. (ethylacetate-isopropyl ether).

NMR (CDCl₃) δ1.69 (3H, s), 1.81 (3H, s), 2.02 (3H, s), 2.05 (3H, s),2.99 (1H, d, J=15.6 Hz), 3.30 (2H, broad s), 3.54 (2H, s), 3.60 (1H, d,J=15.6 Hz), 7.40-7.70 (3H, m), 7.85 (2H, m).

EXAMPLE 100 5-Amino-2,2,6,7-tetramethyl-4-nitro-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 79.6%), m.p. 119°-121° C. (ethanol-ether).

NMR (CDCl₃) δ1.48 (6H, s), 2.20 (3H, s), 2.54 (3H, s), 3.42 (2H, s),8.61 (2H, broad s).

EXAMPLE 1015-Amino-2,2,6,7-tetramethyl-4-dimethylamino-2,3-dihydrobenzofurandihydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 64.5%), m.p. 240°-244° C. (ethanol).

NMR (DMSO-d₆) δ1.42 (6H, s), 2.02 (3H, s), 2.18 (3H, s), 2.63 (6H, s),3.17 (2H, s), 4.94 (2H, broad s).

EXAMPLE 1025-Amino-2,2,4,7-tetramethyl-6-dimethylamino-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 63.2%), m.p. 236°-238° C. (ethanol).

NMR (DMSO-d₆) δ1.41 (6H, s), 2.10 (3H, s), 2.19 (3H, s), 2.72 (6H, s),2.96 (2H, s), 9.66 (2H, broad s).

EXAMPLE 103 5-Amino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran

Sulfuric acid (2.0 mi) was added to a solution of4-amino-2,3,5-trimethylphenol (2.0 g, 13.2 mmol) and 2-methyl-2-propenol(1.15 g, 15.8 mmol) in dichloromethane (20 ml) and the mixture washeated under reflux for 18 hours under an argon atmosphere. The reactionsolution was made weak alkaline with aqueous saturated sodiumbicarbonate solution and the organic layer was separated. The organiclayer was washed with water, dried and then concentrated. The residuewas purified by column chromatography on silica gel eluting withisopropyl ether. The product obtained was recrystallized from hexane toobtain the desired product as crystals (460 mg, yield: 16.9%), m.p.110°-111° C.

NMR (CDCl₃) δ1.45 (6H, s), 2.06 (3H, s), 2.09 (3H, s), 2.13 (3H, s),2.94 (2H, s), 3.26 (2H, broad s).

EXAMPLE 104 2,2,4,6,7-Pentamethyl-5-phenylamino-2,3-dihydrobenzofuran

To a solution of3,5,6-trimethyl-2-(2-methyl-2-propenyl)-4-phenylaminophenol (1.40 g,4.98 mmol) in methanol (30 ml) was added conc. hydrochloric acid (10 ml)with ice-cooling and the mixture was heated with reflux in an argonatmosphere. The reaction mixture was cooled, neutralized with an aqueoussodium bicarbonate solution and extracted with ethyl acetate. Theextract was washed with a saturated saline solution and concentrated.The residue was recrystallized from isopropyl ether to obtain thedesired compound (0.97 g, yield: 69.3%), m.p. 148°-150° C.

NMR (CDCl₃) δ1.49 (6H, s), 2.04 (3H, s), 2.10 (3H, s), 2.12 (3H, s),2.95 (2H, s), 5.03 (1H, broad s), 6.42-6.48 (2H, m), 6.6-6.72 (1H, m),7.08-7.17 (2H, m).

EXAMPLE 1055-(4-Chlorophenylamino)-2,2,4,6,7-pentametyl-2,3-dihydrobenzofuran

According to the same manner as that described in Example 104, thetitled compound was obtained (yield: 60.0%), m.p. 106°-107° C.(isopropyl ether-pentane).

NMR (CDCl₃) δ1.49 (6H, s), 2.02 (3H, s), 2.07 (3H, s), 2.12 (3H, s),2.95 (2H, s), 5.04 (1H, broad s), 6.36 (2H, d, J=8.8 Hz), 7.06 (2H, d,J=8.8 Hz).

EXAMPLE 1065-(4-Methoxyphenylamino)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran

According to the same manner as that described Example 104, the titledcompound was obtained (yield: 61.2%), m.p. 117°-119° C. (isopropylether-pentane).

NMR (CDCl₃) δ1.49 (6H, s), 2.04 (3H, s), 2.09 (3H, s), 2.12 (3H, s),2.95 (2H, s), 3.73 (3H, s), 4.86 (1H, broad s), 6.41 (2H, d, J=9.0 Hz),6.73 (2H, d, J=9.0 Hz).

Reference Example 1 4-Amino-2,3,5-trimethylphenol

Solid Na₂ CO₃ (13.7 g, 129 mmol) was added slowly with stirring at roomtemperature to a solution of sulfanilic acid (49.4 g, 258 mmol) in water(250 ml). After the reaction mixture became a homogeneous solution (whenthe mixture could not be dissolved at the temperature, it could beheated a little), the mixture was cooled with ice and a solution ofNaNO₂ (19.4 g, 280 mmol) in water (50 ml) was added at an innertemperature of below 10° C. Then, this solution was placed in a droppingfunnel. The solution was added dropwise to a mixture of concentratedhydrochloric acid (46 ml) and ice (100 g) over about 10 minutes withstirring under ice cooling at an inner temperature of the droppingfunnel of below 10° C. After the addition was completed, the reactionmixture was stirred for 30 minutes under ice cooling. Next, water (250ml), NaOH (56.8 g, 142 mmol) and 2,3,5-trimethylphenol (35.3 g, 259mmol) were placed in another reaction vessel equipped with a mechanicalstirring apparatus and to this mixture was added dropwise the reactionmixture above with stirring under a stream of nitrogen over 15 minutesin the range of -10° C. to 5° C. At that time ice was properly added tothe ice bath to cool the reaction system in order to keep a temperatureof the contents in the dropping funnel below 10° C. After the additionwas completed, the reaction mixture was heated to 50° C. and Na₂ S₂ O₄(11.9 g, 68.3 mmol) was added. Then the mixture was heated to 80° C. andfurther 5 equal parts of Na₂ S₂ O₄ (214.2 g, 1.23 mol) were added atintervals of 5 minutes. The reaction mixture was stirred for 30 minutesat the same temperature and then cooled. The precipitated crystals werefiltered. The crystals obtained were washed with water, dried and thenrecrystallized from ethyl acetate-isopropyl ether to obtain the desiredcompound (33.0 g, yield: 84.2%), m.p. 153°-154° C.

NMR (CDCl₃) δ2.11 (6H, s), 2.16 (3H, s), 3.55 (3H, broad s), 6.42 (2H,s).

Reference Example 2 4-Amino-2,5-dimethylphenol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 59.7%) m.p. 216°-220° C. (water).

NMR (DMSO-d₆) δ1.94 (3H, s), 1.97 (3H, s), 4.06 (2H, broad s), 6.33 (1H,s), 6.38 (1H, s), 8.04 (1H, s).

Reference Example 3 4-Amino-3,5-dimethylphenol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 52.2%), m.p. 190°-191° C. (water).

NMR (DMSO-d₆) δ2.01 (6H, s), 3.90 (2H, broad s), 6.28 (2H, s), 8.19 (1H,s).

Reference Example 4 4-Formylamino-2,3,5-trimethylphenol

4-Amino-2,3,5-trimethylphenol (100 g, 662 mmol) was dissolved in formicacid (500 ml). The mixture was heated under reflux for 36 hours. Thereaction mixture was poured into ice-cold water. The precipitatedcrystals were filtered, washed with water and dried. The crude crystalsobtained were recrystallized from ethanol to obtain the desired compound(85.9 g, yield: 72.5%), m.p. 219°-220° C.

NMR (CDCl₃) δ2.00 (3H, s), 2.03 (6H, s), 6.53 (1H, s), 8.20 (1H, d,J=1.8 Hz), 9.06 (1H, s), 9.15 (1H, broad s).

Reference Example 5 4-Formylamino-3,5-dimethylphenol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 70.3%), m.p. 239° C. (dichloromethane-isopropylether).

NMR (DMSO-d₆) δ2.05 (6H, s), 6.46 (2H, s), 8.19 (1H, s), 9.13 (1H, broads), 9.16 (1H, s).

Reference Example 6 1-Acetoxy-4-acetylamino-2,3,5-trimethylbenzene

4-Amino-2,3,5-trimethylphenol (26.5 g, 17.5 mmol) was dissolved inpyridine (80 ml). Acetic anhydride (53 ml, 56.2 mmol) was added to thesolution with stirring. After the reaction mixture was stirred for 1hour, the mixture was poured into ice-cold water and crystalsprecipitated were filtered. The crystals were washed with water, driedand then recrystallized from ethyl acetate to obtain the desiredcompound (36.5 g, yield: 88.5%), m.p. 174°-175° C.

NMR (CDCl₃) δ2.00-2.25 (12H, m), 2.31 (3H, s), 6.60-6.90 (2H, m).

Reference Example 7 1-Acetoxy-4-acetylamino-2,3-dimethylbenzene

The title compound was synthesized according to the same manner as thatdescribed above (yield: 88.3%), m.p. 155°-156° C.(dichloromethane-isopropyl ether).

NMR (CDCl₃) δ2.09 (3H, s), 2.14 (3H, s), 2.19 (3H, s), 2.33 (2H, s),6.86 (1H, d, J=8.5 Hz), 7.05 (1H, broad s), 7.37 (1H, d, J=8.5 Hz).

Reference Example 8 1-Acetoxy-4-acetylamino-2,5-dimethylbenzene

The title compound was synthesized according to the same manner as thatdescribed above (yield: 54.9%), m.p. 177° C. (dichloromethane-isopropylether)

NMR (CDCl₃) δ2.12 (3H, s), 2.16 (3H, s), 2.30 (3H, s), 6.81 (1H, s),7.02 (1H, broad s), 7.57 (1H, s).

Reference Example 9 4-Acetylamino-2,3,5-trimethylphenol

A solution of potassium carbonate (27 g, 195 mmol) in water (150 ml) wasadded to a solution of 1-acetoxy-4-acetylamino-2,3,5-trimethylbenzene(66.0 g, 324 mmol) in methanol (300 ml) and the mixture was stirred for1 hour under an argon atmosphere. Aqueous 1N hydrochloric acid solutionwas added to the reaction mixture to make the mixture weakly acid andthe resulting mixture was diluted with water. Crystals precipitated werefiltered, washed with water, dried and then recrystallized from ethylacetateisopropyl ether to obtain the desired compound (36.8 g, yield:67.9%), m.p. 189°-190° C. (ethyl acetate-isopropyl ether).

NMR (DMSO-d₆) δ1.98 (3H, s), 1.99 (6H, s), 2.01 (3H, s), 6.50 (1H, s),8.95 (1H, s), 9.00 (1H, s).

Reference Example 10 4-Acetylamino-2,3-dimethylphenol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 40.0%), m.p. 184°-185° C.(dichloromethane-isopropyl ether).

NMR (CDCl₃) δ2.13 (3H, s), 2.16 (3H, s), 2.18 (3H, s), 6.66 (1H, d,J=8.5 Hz), 7.01 (1H, d, J=8.5 Hz), 7.22 (1H, broad s), 7.29 (1H, s).

Reference Example 11 4-Acetylamino-2,5-dimethylphenol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 92.1%), m.p. 183° C. (dichloromethane-isopropylether).

NMR (DMSO-d₆) δ1.97 (3H, s), 2.04 (6H, s), 6.58 (1H, s), 6.91 (1H, s),9.03 (2H, s).

Reference Example 124-Formylamino-2,3,5-trimethyl-1-(2-methyl-2-propenyloxy)benzene

Potassium carbonate (74.0 g, 0.54 mol) was added to a solution of4-formylamino-2,3,5-trimethylphenol (85.5 g, 0.48 mol) and methallylchloride (45.3 g, 0.5 mol) in dimethylformamide (300 ml) and the mixturewas stirred at 80° C. for 3 hours under an argon atmosphere. Thereaction mixture was poured into ice-cold water. Crystals precipitatedwere filtered, washed with water and dried. The crude crystals obtainedwere recrystallized from isopropyl ether to obtain the desired compound(80.0 g, yield: 71.6%), m.p. 144°-145° C.

NMR (CDCl₃) δ1.84 (3H, m), 2.17 (3H, s), 2.19 (1.5H, s), 2.22 (3H, s),2.26 (1.5H, s), 4.40 (1H, s), 4.42 (1H, s), 4.99 (1H, m), 5.11 (1H,broad s), 6.60 (1H, s), 6.75 (1H, m), 7.98 (0.5H, d, J=12.0 Hz), 8.41(0.5H, s).

Reference Example 134-Acetylamino-2,3,5-trimethyl-1-(2-methyl-2-propenyloxy)benzene

The title compound was synthesized according to the same manner as thatdescribed above (yield: 92.6%), m.p. 149°-150° C. (isopropyl ether).

NMR (CDCl₃) δ1.84 and 1.86 (3H, s), 2.14 (3H, s), 2.16 (3H, s), 2.19(3H, s), 2.20 (3H, s), 4.38 and 4.32 (2H, s), 4.98 (1H, m), 5.11 (1H,broad s), 6.58 and 6.50 (1H, s), 6.60 and 6.72 (1H, broad s).

Reference Example 14 2,3,5-Trimethyl-1-(2-methyl-2-propenyloxy)benzene

The title compound was synthesized according to the same manner as thatdescribed above (yield: 98.9%), b.p. 108°-112° C. (10 mmHg).

NMR (CDCl₃) δ1.87 (3H, s), 2.17 (3H, s), 2.26 (3H, s), 2.30 (3H, s),4.42 (2H, s), 5.00 (1H, broad s), 5.15 (1H, broad s), 6.55 (1H, broads), 6.64 (1H, broad s).

Reference Example 154-Acetylamino-2,3-dimethyl-1-(2-methyl-2-propenyloxy)benzene

The title compound was synthesized according to the same manner as thatdescribed above (yield: 86.2%), m.p. 154°-156° C.(dichloromethane-isopropyl ether).

NMR (CDCl₃) δ1.84 (3H, s), 2.16 (3H, s), 2.19 (3H, s), 2.21 (3H, s),4.41 (2H, s), 4.98 (1H, s), 5.12 (1H, s), 6.70 (1H, d, J=8.8 Hz), 6.89(1H, broad s), 7.20 (1H, d, J=8.8 Hz).

Reference Example 164-Acetylamino-2,5-dimethyl-1-(2-methyl-2-propenyloxy)benzene

The title compound was synthesized according to the same manner as thatdescribed above (yield: 84.3%), m.p. 128°-132° C.(dichloromethane-isopropyl ether).

NMR (CDCl₃) δ1.60 and 2.17 (3H, s), 1.84 (3H, s), 2.20 (6H, s), 4.40(2H, s), 4.98 (1H, s), 5.11 (1H, s), 6.63 (1H, s), 6.80 (1H, broad s),7.28 (1H, s).

Reference Example 174-Formylamino-3,5-dimethyl-1-(2-methyl-2-propenyloxy)benzene

The title compound was synthesized according to the same manner as thatdescribed above (yield: 98.4%), m.p. 128°-129° C. (isopropyl ether).

NMR (DMSO-d₆) δ1.77 (3H, s), 2.11 (6H, s), 4.43 (2H, s), 4.95 (1H, s),05 (1H s), 6 68 (2H, s), 8 22 (1H, s), 9.26 (1H, s).

Reference Example 184-Formylamino-3,5-dimethyl-2-(2-methyl-2-propenyl)-1-(2-methyl-2-propenyloxy)benzene

The title compound was synthesized according to the same manner as thatdescribed above (yield: 98.4%), m.p. 109° C. (dichloromethane-isopropylether).

NMR (DMSO-d₆) δ1.72 (3H, s), 1.76 (3H, s), 2.01 (3H, s), 2.12 (3H, s),3.32 (2H, s), 4.30 (1H, s), 4.41 (2H, s), 4.66 (1H, s), 4.93 (1H, s),5.06 (1H, s), 6.73 (1H, s), 8.22 (1H, s), 9.27 (1H, s).

Reference Example 194-Formylamino-2,3,5-trimethyl-6-(2-methyl-2-propenyl)phenol

4-Formylamino-2,3,5-trimethyl-1-(2-methyl-2-propenyloxy) benzene (80 g,0.34 mol) was dissolved in N,N-diethylaniiine (500 ml). The solution washeated at 200° C. for 3 hours. The solution was allowed to cool. Whencrystals were precipitated, hexane was added. The crystals precipitatedwere filtered to obtain the desired compound (75.2 g, yield: 94.0%). Thecrude crystals were recrystallized from ethyl acetate-isopropyl ether toobtain crystals, m.p. 163°-164° C.

NMR (CDCl₃) δ1.80 (3H, s), 2.16 (3H, s), 2.17 (1.5H, s), 2.19 (1.5H, s),2.20 (1.5H, s), 2.21 (1.5H, s), 3.38 (2H, broad s), 4.65 (1H, m), 4.88(1H, m), 5.16 (0.5H, s), 5.19 (0.5H, s), 6.70 (1H, m), 7.95 (0.5H, d,J=12.0 Hz), 8.42 (0.5H, d, J=1.8 Hz).

Reference Example 204-Acetylamino-2,3,5-trimethyl-6-(2-methyl-2-propenyl)phenol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 97.7%), m.p. 209°-210° C. (ethylacetate-isopropyl ether).

NMR (CDCl₃) δ1.73 (3H, s), 1.94 (3H, s), 1.99 (6H, s), 2.09 (3H, s),3.33 (2H, m), 4.28 (1H, broad s), 4.64 (1H, broad s), 7.86 (1H, broads), 9.00 (1H, s).

Reference Example 21 2,3,5-Trimethyl-6-(2-methyl-2-propenyl)phenol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 80.6%) b.p. 124°-126° C. (10 mmHg).

NMR (CDCl₃) δ1.79 (3H, s), 2.14 (3H, s), 2.24 (6H, s), 3.37 (2H, s),4.74 (1H, m), 4.88 (1H, m), 5.08 (1H, s), 6.63 (1H, s).

Reference Example 224-Acetylamino-2,3-dimethyl-6-(2-methyl-2-propenyl)phenol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 91.8%), m.p. 149°-151° C.(dichloromethane-isopropyl ether).

NMR (CDCl₃) δ1.72 (3H, s), 2.12 (3H, S), 2.16 (3H, s), 2.17 (3H, s),3.32 (2H, s), 4.89-4.94 (2H, m), 5.39 (1H, s), 6.92 (1H, broad s), 7.00(1H, s).

Reference Example 234-Acetylamino-2,5-dimethyl-6-(2-methyl-2-propenyl)phenol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 98.7%), m.p. 183°-185° C.(dichloromethane-isopropyl ether).

NMR (CDCl₃) δ1.79 (3H, s), 2.11-2.22 (9H, m), 3.38 (2H, s), 4.60 (1H,s), 4.83 (1H, s), 7.11 (1H, s).

Reference Example 244-Formylamino-3,5-dimethyl-2-(2-methyl-2-propenyl)phenol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 80.8%), m.p. 207°-209° C. (isopropyl ether).

NMR (DMSO-d₆) δ1.71 (3H, s), 1.97 (3H, s), 2.04 (3H, s), 3.25 (2H, s),4.33 (1H, s), 4.65 (1H, s), 6.55 (1H, s), 8.19 (1H, s), 9.09 (1H, s).

Reference Example 252,6-Bis(2-methyl-2-propenyl)-4-formylamino-3,5-dimethylphenol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 84.2%), m.p. 169°-170° C. (isopropyl ether).

NMR (DMSO-d₆) δ1.72 (6H, s), 1.98 (6H, s), 3.33 (4H, s), 4.28 (2H, s),4.65 (2H, s), 7.86 (1H, s), 8.20 (1H, s), 9.19 (1H, s).

Reference Example 26 2-Bromo-3,5,6-trimethylanisole

A solution of t-butylamine (73 g, 1.0 mol) in toluene (1L) was cooled to-20° to 30° C. and bromine (79.9 g, 0.5 mol) was added dropwise overabout 10 minutes. The reaction mixture was cooled to -70° to -75° C. andto this mixture was added dropwise 2,3,5-trimethylphenol (68 g, 0.5 mol)which was dissolved in the smallest amount of dichloromethane. Thereaction mixture was stirred at the same temperature for 30 minutes andat room temperature for 3 hours. Then the mixture was washed with water,dried and concentrated. Sodium hydride (60% content, 22 g, 0.55 mol) wasplaced in another reaction vessel and washed with hexane 2 or 3 times,and then dimethylformamide (500 ml) was added. A solution of theconcentrated residue above in dimethylformamide (50 ml) was added to themixture. The reaction mixture was stirred for 30 minutes and iodomethane(34.2 ml, 0.55 mol) was added dropwise. The resulting mixture wasstirred for additional 1 hour. The reaction mixture was diluted withwater and the product was extracted with isopropyl ether. The extractwas washed with water, dried and then concentrated. The concentratedresidue was distilled under reduced pressure. The fractions havingboiling point of 130° to 135° C. were collected to obtain the desiredcompound (32.3 g, yield: 28.6%).

NMR (CDCl₃) δ2.20 (3H, s), 2.21 (3H, s), 2.34 (3H, s), 3.76 (3H, s),6.83 (1H, s).

Reference Example 271-(2-Methoxy-3,4,6-trimethylphenyl)-1-phenyl-2-methylpropanol

A solution of 2-bromo-3,5,6-trimethylanisole (3.0 g, 13.1 mmol) intetrahydrofuran (20 ml) was cooled to -78° C. and n-butyllithium (1.6Msolution in hexane, 8.2 ml, 13.1 mmol) was added dropwise. The reactionmixture was stirred at the same temperature for 15 minutes. Then asolution of isobutyrylbenzene (1.94 g, 13.1 mmol) in tetrahydrofuran (5ml) was added dropwise and the resulting mixture was stirred at roomtemperature for additional 30 minutes. The reaction mixture was dilutedwith water and the product was extracted with isopropyl ether. Theextract was washed with water, dried and then concentrated. The residuewas crystallized from hexane to obtain the desired compound (3.13 g,yield: 80.2%), m.p. 80°-81° C.

NMR (CDCl₃) δ0.88 (3H, d, J=6.6 Hz), 1.05 (3H, d, J=6.4 Hz), 2.07 (3H,s), 2.18 (3H, s), 2.58 (3H, s), 2.82 (1H, qq, J=6.4 Hz and 6.6 Hz), 2.90(3H, s), 6.18 (1H, broad s), 6.75 (1H, s), 7.10-7.30 (3H, m), 7.40-7.50(2H, m).

Reference Example 281-(4-Fluorophenyl)-1-(2-methoxy-3,4,6-trimethylphenyl)-2-methylpropanol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 97.9%), m.p. 102°-103° C. (hexane).

NMR (CDCl₃) δ0.88 (3H, d, J=6.6 Hz), 1.02 (3H, d, J=6.4 Hz), 2.08 (3H,s), 2.19 (3H, s), 2.53 (3H, s), 2.80 (1H, qq, J=6.4 Hz and 6.6 Hz), 2.97(3H, s), 6.23 (1H, broad s), 6.75 (1H, s), 6.95 (2H, t, J=8.8 Hz), 7.40(2H, dd, J=8.8 Hz and 5.4 Hz).

Reference Example 291-(2-Methoxy-3,4,6-trimethylphenyl)-1-(4-methylphenyl)-2-methylpropanol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 80.6%), m.p. 103°-104° C. (hexane).

NMR (CDCl₃) δ0.89 (3H, d, J=6.6 Hz), 1.03 (3H, d, J=6.4 Hz), 2.09 (3H,s), 2.19 (3H, s), 2.30 (3H, s), 2.56 (3H, s), 2.82 (1H, qq, J=6.4 Hz and6.6 Hz), 2.95 (3H, s), 6.18 (1H, broad s), 6.75 (1H, s), 7.07 (2H, d,J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz).

Reference Example 301-(2-Methoxy-3,4,6-trimethylphenyl)-1-(4-propylphenyl)-2-methylpropanol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 74.6%), m.p. 59°-60° C. (hexane).

NMR (CDCl₃) δ0.87 (3H, t, J=6.4 Hz), 0.90 (3H, d, J=6.6 Hz), 1.03 (3H,d, J=6.4 Hz), 1.60 (2H, sextet, 6.4 Hz), 2.08 (3H, s), 2.18 (3H, s),2.54 (2H, t, J=6.4 Hz), 2.56 (3H, s), 2.84 (1H, qq, J=6.6 Hz and 6.4Hz), 2.93 (3H, s), 6.15 (1H, broad s), 7.06 (2H, d, J=8.4 Hz), 7.33 (2H,d, J=8.4 Hz).

Reference Example 311-(2-Methoxy-3,4,6-trimethylphenyl)-1-(4-pentylphenyl)-2-methylpropanol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 75.4%), m.p. 55°-56° C. (hexane).

NMR (CDCl₃) δ0.85 (3H, t, J=6.2 Hz), 0.90 (3H, d, J=6.6 Hz), 1.03 (3H,d, J=6.6 Hz), 1.28 (4H, m), 1.56 (2H, quintet, J=6.8 Hz), 2.08 (3H, s),2.18 (3H, s), 2.54 (2H, t, J=7.5 Hz), 2.55 (3H, s), 2.84 (1H, septet,J=6.6 Hz), 2.92 (3H, s), 6.15 (1H, broad s), 6.75 (1H, s), 7.07 (2H, d,J=8.0 Hz), 7.34 (2H, d, J=8.0 Hz).

Reference Example 321-(4-Isopropylphenyl)-1-(2-methoxy-3,4,6-trimethylphenyl)-2-methylpropanol

The title compound was synthesized as oil according to the same manneras that described above (yield: 65.1%).

NMR (CDCl₃) δ0.91 (3H, d, J=6.6 Hz), 1.02 (3H, d, J=6.6 Hz), 1.20 (6H,d, J=7.0 Hz), 2.08 (3H, s), 2.17 (3H, s), 2.54 (3H, s), 2.84 (1H,septet, J=6.6 Hz), 2.93 (3H, s), 2.96 (1H, septet, J=7.0 Hz), 6.16 (1H,broad s), 6.74 (1H, s), 7.10 (2H, d, J=8.4 Hz), 7.90 (2H, d, J=8.4 Hz).

Reference Example 331-(2-Methoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)-2-methylpropanol

The title compound was synthesized as oil according to the same mannerthat as described above (yield: 68.9%).

NMR (CDCl₃) δ0.93 d, J=6.6 Hz), 1.03 (3H, d, (3H, J=6.6 Hz), 2.09 (3H,s), 2.19 (3H, s), 2.51 (3H, s), 2.90 (1H, septet, J=6.6 Hz), 3.05 (3H,s), 6.29 (1H, broad s), 6.76 (1H, s), 7.22 (1H, dd, J=4.aHz and 8.0 Hz),7.79 (1H, dt, J=2.0 Hz and 8.0 Hz), 8.43 (1H, dd, J=2.0 Hz and 4.8 Hz),8.70 (1H, d, J=2.0 Hz).

Reference Example 341-(2-Methoxy-3,4,6-trimethyl)-1-(4-dimethylaminophenyl)-2-methylpropanol

The title compound was synthesized according to the same manner as thatdescribed above (yield: 59.1%), m.p. 95°-97° C. (hexane).

NMR (CDCl₃) δ0.93 (3H, d, J=6.6 Hz), 1.00 (3H, d, J=6.4 Hz), 2.08 (3H,s), 2.18 (3H, s), 2.53 (3H, s), 2.82 (1H, qq, J=6.4 Hz and 6.6 Hz), 2.90(6H, s), 2.99 (3H, s), 6.12 (1H, broad s), 6.66 (2H, d, J=9.0 Hz), 6.74(1H, s), 7.28 (2H, d, J=9.0 Hz).

Reference Example 353-(2-Methoxy-3,4,6-trimethylphenyl)-2,4-dimethylpentan-3-ol

The title compound was synthesized as oil according to the same manneras that described above (yield: 11.6%).

NMR (CDCl₃) δ0.78 (6H, d, J=6.6 Hz), 1.03 (6H, d, J=6.6 Hz), 2.15 (3H,s), 2.19 (3H, s), 2.42 (3H, s), 2.45 (2H, septet, J=6.6 Hz), 3.73 (3H,s), 6.75 (1H, s), 6.88 (1H, s).

Reference-Example 365-Acetylamino-2,2,6,7-tetramethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed in Example 3 (yield: 71.9%), m.p. 163°-164° C. (ethanol).

NMR (CDCl₃) δ1.45 (6H, s), 2.10 (3H, s), 2.11 (3H, s), 2.17 (3H, s),2.98 (2H, s), 7.00 (1H, s), 7.33 (1H, broad s).

Reference Example 375-Acetylamino-2,2,4,7-tetramethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 67.3%), m.p. 161°-162° C. (isopropyl ether).

NMR (CDCl₃) δ1.47 (6H, s), 2.06 (3H, s), 2.13 (3H, s), 2.14 (3H, s),2.93 (2H, s), 6.81 (1H, broad s), 6.95 (1H, s).

Reference Example 38 5-Amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 43.0%), m.p. 215°-217° C. (isopropanol).

NMR (DMSO-d₆) δ1.40 (6H, s), 2.22 (3H, s), 2.29 (3H, s), 2.94 (2H, s),6.49 (1H, s), 9.58 (2H, broad s).

Reference Example 39 5-Amino-2,2,6,7-tetramethyl-2,3-dihydrobenzofuranhydrochloride

The title compound was synthesized according to the same manner as thatdescribed above (yield: 38.7%), m.p. 235°-238° C. (ethanol).

NMR (CDCl₃) δ1.45 (6H, s), 2.13 (3H, s), 2.40 (3H, s), 2.97 (2H, s),7.27 (2H, s), 10.23 (2H, broad s).

Reference Example 402,2,4,6,7-Pentamethyl-3-phenyl-2,3-dihydrobenzofuran

1-(2-Methoxy-3,4,6-trimethylphenyl)-1-phenyl-2-methylpropanol (3.1 g,10.4 mmol) was suspended in 48% hydrobromic acid (20 ml). The suspensionwas heated under reflux for 18 hours. The product was extracted withisopropyl ether, washed with water, dried and then concentrated. Theresidue was crystallized from ethanol to obtain the desired compound(2.43 g, yield: 87.8%), m.p. 86°-87° C.

NMR (CDCl₃) δ1.02 (3H, s), 1.51 (3H, s), 1.84 (3H, s), 2.15 (3H, s),2.24 (3H, s), 4.13 (1H, s), 6.49 (1H, s), 6.70-7.40 (5H, m).

Reference Example 413-(4-Fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 83.5%), m.p. 109°-110° C. (methanol).

NMR (CDCl₃) δ1.02 (3H, s), 1.49 (3H, s), 1.83 (3H, s), 2.14 (3H, s),2.24 (3H, s), 4.10 (1H, s), 6.49 (1H, s), 6.60-7.20 (4H, m).

Reference Example 422,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 87.7%), m.p. 117°-118° C. (methanol).

NMR (CDCl₃) δ1.02 (3H, s), 1.50 (3H, s), 1.85 (3H, s), 2.15 (3H, s),2.24 (3H, s), 2.31 (3H, s), 4.10 (1H, s), 6.49 (1H, s), 6.50-7.20 (4H,m).

Reference Example 432,2,4,6,7-Pentamethyl-3-(4-propylphenyl)-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 84.9%), m.p. 69°-70° C. (methanol).

NMR (CDCl₃) δ0.90 (3H, t, J=7.2 Hz), 1.02 (3H, s), 1.50 (3H, s), 1.61(2H, sextet, J=8.0 Hz), 1.84 (3H, s), 2.15 (3H, s), 2.24 (3H, s), 2.55(2H, t, J=8.0 Hz), 4.10 (1H, s), 6.49 (1H, s), 6.60-7.20 (4H, m).

Reference Example 442,2,4,6,7-Pentamethyl-3-(4-pentylphenyl)-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 70.7%).

NMR (CDCl₃) δ0.88 (3H, t, J=4.6 Hz), 1.03 (3H, s), 1.30 (4H, m), 1.50(3H, s), 1.56 (2H, m), 1.85 (3H, s), 2.15 (3H, s), 2.24 (3H, s), 2.56(2H, t, J=8.0 Hz), 4.10 (1H, s), 45 (1H, s), 6.60-7.20 (4H, m).

Reference Example 453-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 65.1%).

NMR (CDCl₃) δ1.02 (3H, s), 1.21 (6H, d, J=7.0 Hz), 1.49 (3H, s), 1.84(3H, s), 2.14 (3H, s), 2.24 (3H, s), 2.95 (1H, septet, J=7.0 Hz), 4.09(1H, s), 6.48 (1H, s), 6.70-7.20 (4H, m).

Reference Example 462,2,4,6,7-Pentamethyl-3-(3-pyridyl)-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 77.1%).

NMR (CDCl₃) δ1.05 (3H, s), 1.53 (3H, s), 1.84 (3H, s), 2.14 (3H, s),2.24 (3H, s), 4.14 (1H, s), 6.50 (1H, s), 7.18 (2H, m), 8.35 (1H, m),8.48 (1H, t, J=3.2 Hz).

Reference Example 472,2,4,6,7-Pentamethyl-3-(4-dimethylaminophenyl)-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 88.1%), m.p. 124°-125° C. (methanol)

NMR (CDCl₃) δ1.03 (3H, s), 1.48 (3H, s), 1.85 (3H, s), 2.14 (3H, s),2.23 (3H, s), 2.91 (6H, s), 4.04 (1H, s), 6.47 (1H, s), 6.55-7.00 (4H,m).

Reference Example 483-(4-Isopropyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 88.2%).

NMR (CDCl₃) δ0.73 (3H, d, J=6.8 Hz), 0.98 (3H, d, J=7.2 Hz), 1.21 (3H,s), 1.57 (3H, s), 2.06 (3H, s), 2.10 (1H, m), 2.20 (3H, s), 2.22 (3H,s), 2.73 (1H, d, J=2.8 Hz), 6.49 (1H, s).

Reference Example 49 2,2,4,5,6-Pentamethyl-7-nitro-2,3-dihydrobenzofuran

The mixed solution of acetic anhydride (5 ml) and acetic acid (5 ml) wascooled and nitric acid (5 ml) was added cautiously with stirring. Then,a solution of 2,2,4,5,6-pentamethyl-2,3-dihydrobenzofuran (2.9 g, 13.9mmol) in acetic anhydride (5 ml) was added dropwise and the mixture wasstirred for 30 minutes. The reaction mixture was poured into ice-coldwater and the product was extracted with ethyl acetate. The extract waswashed with saturated sodium bicarbonate solution, dried andconcentrated. The residue was purified by column chromatography onsilica gel (hexane-isopropyl ether, 9:1) and crystallized from methanolto obtain the desired compound (0.35 g, yield: 9.8% yield), m.p.100°-101° C.

NMR (CDCl₃) δ1.51 (6H, s), 2.14 (3H, s), 2.17 (3H, s), 2.24 (3H, s),2.99 (2H, s).

Reference Example 50

2,2,4,6,7-Pentamethyl-5-nitro-3-phenyl-2,3-dihydrobenzofuran

The mixed solution of acetic anhydride (3 ml) and acetic acid (3 ml) wascooled and nitric acid (3 ml) was added cautiously with stirring. Then asolution of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydrobenzofuran (3.7 g,13.9 mmol) in acetic anhydride (3 ml) was added dropwise and the mixturewas stirred for 30 minutes. The reaction mixture was poured intoice-cold water and the product was extracted with ethyl acetate. Theextract was washed with saturated sodium bicarbonate solution, dried andconcentrated. The residue was purified by column chromatography onsilica gel (hexane-isopropyl ether, 9:1) and crystallized from methanolto obtain the desired compound (2.08 g, yield: 48.1%), m.p. 155°-156° C.

NMR (CDCl₃) δ1.04 (3H, s), 1.52 (3H, s), 1.83 (3H, s), 2.18 (3H, s),2.20 (3H, s), 4.15 (1H, s), 6.85 (2H, m), 7.26 (3H, m).

Reference Example 513-(4-Fluorophenyl)-2,2,4,6,7-pentamethyl-5-nitro-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 66.3%), m.p. 94°-95° C. (methanol).

NMR (CDCl₃) δ1.04 (3H, s), 1.50 (3H, s), 1.84 (3H, s), 2.18 (3H, s),2.20 (3H, s), 4.14 (1H, s), 6.50-7.20 (4H, m).

Reference Example 522,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-5-nitro-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 56.0%).

NMR (CDCl₃) δ1.05 (3H, s), 1.50 (3H, s), 1.84 (3H, s), 2.18 (3H, s),2.20 (3H, s), 2.32 (3H, s), 4.11 (1H, s), 6.50-7.20 (4H, m).

Reference Example 532,2,4,6,7-Pentamethyl-5-nitro-3-(4-propylphenyl)-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 65.8%).

NMR (CDCl₃) δ0.91 (3H, t, J=7.4 Hz), 1.04 (3H, s), 1.50 (3H, s), 1.61(2H, sextet, J=7.4 Hz), 1.84 (3H, s), 2.18 (3H, s), 2.20 (3H, s), 2.55(2H, t, J=7.4 Hz), 4.12 (1H, s), 6.50-7.20 (4H, m).

Reference Example 542,2,4,6,7-Pentamethyl-5-nitro-3-(4-pentylphenyl)-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 76.4%).

NMR (CDCl₃) δ0.89 (3H, t, J=6.6 Hz), 1.04 (3H, s), 1.30 (4H, m), 1.50(3H, s), 1.59 (2H, m), 1.84 (3H, s), 2.18 (3H, s), 2.20 (3H, s), 2.56(2H, t, J=7.8 Hz), 4.11 (1H, s), 5.50-7.20 (4H, m).

Reference Example 553-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-5-nitro-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 48.0%), m.p. 109°-110° C. (methanol).

NMR (CDCl₃) δ1.04 (3H, s), 1.22 (6H, d, J=6.8 Hz), 1.50 (3H, s), 1.84(3H, s), 2.18 (3H, s), 2.20 (3H, s), 2.87 (1H, septet, J=6.8 Hz), 4.12(1H, s), 6.60-7.20 (4H, m).

Reference Example 562,2,4,6,7-Pentamethyl-5-nitro-3-(3-pyridyl)-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 60.7%).

NMR (CDCl₃) δ1.07 (3H, s), 1.54 (3H, s), 1.84 (3H, s), 2.19 (3H, s),2.21 (3H, s), 4.18 (1H, s), 7.05-7.35 (2H, m), 8.25-8.60 (2H, m).

Reference Example 572,2,4,6,7-Pentamethyl-3-(4-dimethylamino-3-nitrophenyl)-5-nitro-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 24.2%).

NMR (CDCl₃) δ1.13 (3H, s), 1.51 (3H, s), 1.91 (3H, s), 2.19(3H, s), 2.21(3H, s), 2.81 (6H, s), 4.12 (1H, s), 7.00-7.80 (3H, m).

Reference Example 583-Isopropyl-2,2,4,6,7-pentamethyl-5-nitro-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 62.0%).

NMR (CDCl₃) δ0.72 (3H, d, J=7.0 Hz), 0.98 (3H, d, J=7.2 Hz), 1.23 (3H,s), 1.59 (3H, s), 2.09 (1H, m), 2.10 (3H, s), 2.16 (3H, s), 2.21 (3H,s), 2.78 (1H, d, J=2.8 Hz).

Reference Example 592,4,6,7-Tetramethyl-5-nitro-2-piperidinomethyl-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 62.8%).

NMR (CDCl₃) δ1.30-1.60 (6H, m), 1.42 (3H, s), 2.08 (3H, s), 2.14 (6H,s), 2.50 (6H, m), 2.78 (1H, d, J=15.6 Hz), 3.18 (1H, d, J=15.6 Hz).

Reference Example 602,4,6,7-Tetramethyl-2-morpholinomethyl-5-nitro-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 59.0%).

NMR (CDCl₃) δ1.44 (3H, s), 2.07 (3H, s), 2.15 (6H, s), 2.57 (6H, m),2.80 (1H, d, J=15.6 Hz), 3.21 (1H, d, J=15.6 Hz), 3.66 (4H, t, J=4.4Hz).

Reference Example 612,4,6,7-Tetramethyl-2-[2-(dimethylamino)ethyl]-5-nitro-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 53.0%).

NMR (CDCl₃) δ1.44 (3H, s), 1.62 (2H, m), 2.10 (3H, s), 2.13 (3H, s),2.15 (3H, s), 2.24 (6H, s), 2.40 (2H, m), 2.87 (1H, d, J=15.6 Hz), 3.06(1H, d, J=15.6 Hz).

Reference Example 622,4,6,7-Tetramethyl-5-nitro-2-(2-piperidinoethyl)-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed above (yield: 46.3%), m.p. 247°-250° C.

NMR (CDCl₃) δ1.50 (3H, s), 1.90 (2H, m), 2.08 (3H, s), 2.13 (3H, s),2.14 (3H, s), 2.18 (4H, m), 2.40 (2H, m), 2.64 (2H, m), 2.97 (1H, d,J=15.6 Hz), 3.07 (2H, m), 3.17 (1H, d, J=15.6 Hz), 3.55 (2H, m).

Reference Example 63 2,2,4,5,6-Pentamethyl-2,3-dihydrobenzofuran

3,4,5-Trimethylphenol (5.0 g, 36.7 mmol) and 2-methyl-2-propenol (3.2 g,44.0 mmol) were added to formic acid (50 ml). The mixture was heatedunder reflux for 3 hours. The reaction mixture was diluted withisopropyl ether, washed with water and saturated sodium bicarbonatesolution, dried and concentrated. The residue was purified by columnchromatography on silica gel (hexane-isopropyl ether, 97:3) to obtainthe desired compound (2.9 g, yield: 41.5%) as oil.

NMR (CDCl₃) δ1.45 (6H, S), 2.09 (3H, S), 2.14 (3H, s), 2.23 (3H, S),2.93 (2H, S), 6.44 (1H, s).

Reference Example 645-Bromo-2-bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

The title compound was synthesized according to the same manner as thatdescribed in Example 29 (yield: 67.7%), m.p. 60°-61° C. (methanol).

NMR (CDCl₃) δ1.61 (3H, s), 2.15 (3H, s), 2.27 (3H, s), 2.35 (3H, s),2.67 (1H, d, J=15.6 Hz), 3.33 (1H, d, J=15.6 Hz), 3.51 (2H, s).

Reference Example 65

2-Bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

Triethylamine (5.0 ml, 35.6 mmol) was added to a solution of5-bromo-2-bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (12.4 g,35.6 mmol) in ethanol (100 ml). Catalytic hydrogenation decompositionreaction was carried out on 5% palladium carbon under a hydrogenatmosphere. After the completion of the reaction, the catalyst wasfiltered and the filtrate was concentrated. The residue was dissolved inisopropyl ether, washed with water, dried and the solvent was distilledoff. The residue was crystallized from methanol to obtain the desiredcompound (8.84 g, yield: 92.2%), m.p. 39°-40° C.

NMR (CDCl₃) δ1.63 (3H, s), 2.08 (3H, s), 2.17 (3H, s), 2.21 (3H, s),2.92 (1H, d, J=15.8 Hz), 3.26 (1H, d, J=15.8 Hz), 3.48 (1H, d, J=15.6Hz), 3.58 (1H, d, J=15.6 Hz), 6.53 (1H, s).

Reference Example 662,4,6,7-Tetramethyl-2-piperidinomethyl-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described in Example 57 (yield: 81.6%).

NMR (CDCl₃) δ1.30-1.60 (6H, m), 1.44 (3H, s), 2.05 (3H, s), 2.15 (3H,s), 2.19 (3H, s), 2.40-2.65 (6H, m), 2.76 (1H, d, J=15.2 Hz), 3.06 (1H,d, J=15.2 Hz), 6.47 (1H, s).

Reference Example 672,4,6,7-Tetramethyl-2-morpholinomethyl-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 99.8%).

NMR (CDCl₃) δ1.44 (3H, s), 2.04 (3H, s), 2.15 (3H, s), 2.19 (3H, s),2.40-2.70 (6H, m), 2.79 (1H, d, J=15.4 Hz), 3.08 (1H, d, J=15.4 Hz),3.67 (4H, t, J=4.6 Hz), 6.48 (1H, s).

Reference Example 682-Cyanomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran

2-Bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (6.5 g, 18.6mmol) was dissolved in dimethylsufoxide (30 ml). Sodium cyanide (1.43 g,88 mmol) was added and the resulting mixture was stirred at 80° C. for18 hours. The reaction mixture was diluted with water and the productwas extracted with ethyl acetate. The extract was washed with water,dried and concentrated. The residue was purified by columnchromatography on silica gel (hexaneisopropyl ether, 2:1). The crudecrystals obtained were recrystallized from methanol to obtain thedesired compound (4.1 g, yield: 79.7%), m.p. 58°-59° C.

NMR (CDCl₃) δ1.66 (3H, s), 2.07 (3H, s), 2.16 (3H, s), 2.20 (3H, s),2.68 (1H, d, J=10.8 Hz), 2.75 (1H, d, J=10.8 Hz), 3.00 (1H, d, J=15.8Hz), 3.12 (1H, d, J=15.8 Hz), 6.54 (1H, s).

Reference Example 69 2,4,6,7-Tetramethyl-2,3-dihydrobenzofuran-2-ylacetic acid

A solution of sodium hydroxide (12.0 g, 300 mmol) in water (30 ml) wasadded to a solution of2-cyanomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (6.9 g, 32.1mmol) in methanol (30 ml) and the mixture was heated under reflux for 18hours. The reaction mixture was made weakly acidic with 6N hydrochloricacid and the product was extracted with ethyl acetate. The extract waswashed with water, dried and concentrated. The residue was crystallizedfrom ethyl acetate-hexane to obtain the desired compound (6.0 g, yield:79.9%), m.p. 139°-140° C.

NMR (DMSO-d₆) δ1.61 (3H, s), 2.07 (3H, s), 2.16 (3H, s), 2.21 (3H, s),2.78 (1H, d, J=10.8 Hz), 2.85 (1H, d, J=10.8 Hz), 2.97 (1H, d, J=15.4Hz), 3.21 (1H, d, J=15.4 Hz), 6.52 (1H, s), 8.50 (1H, broad s).

Reference Example 70N,N-Dimethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-ylacetamide

To a solution of 2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl aceticacid (3.0 g, 12.8 mmol) in dimethylformamide (30 ml) were added1-hydroxy-1H-benzotriazole monohydrate (HOBt) (2.1 g, 14.1 mmol) and1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) (3.7g, 19.2 mmol). The mixture was stirred at room temperature for 1 hour.Then, 50% dimethylamine aqueous solution (3 ml) was added and theresulting mixture was stirred for additional 30 minutes. The reactionmixture was diluted with water and the product was extracted with ethylacetate. The extract was washed with water, dried and concentrated. Theresidue was purified by column chromatography on silica gel (isopropylether) to obtain the desired compound (3.1 g, yield: 92.6% yield) asoil.

NMR (CDCl₃) δ1.59 (3H, s), 2.07 (3H, s), 2.14 (3H, s), 2.20 (3H, s),2.77 (1H, d, J=15.0 Hz), 2.88 (1H, d, J=15.0 Hz), 2.94 (3H, s), 3.00(1H, d, J=15.8 Hz), 3.03 (3H, s), 3.27 (1H, d, J=15.8 Hz), 6.50 (1H, s).

Reference Example 71(2,4,6,7-Tetramethyl-2,3-dihydrobenzofuran-2-yl)-acetyl-1-piperidine

The title compound was synthesized as oil according to the same manneras that described above (yield: 90.7%).

NMR (CDCl₃) δ1.55 (3H, s), 1.60 (6H, m), 2.06 (3H, s), 2.13 (3H, s),2.19 (3H, s), 2.78 (1H, d, J=14.8 Hz), 2.90 (1H, d, J=14.8 Hz), 2.97(1H, d, J=15.8 Hz), 3.24 (1H, d, J=15.8 Hz), 3.40-3.60 (4H, m), 6.50(1H, s).

Reference Example 722,4,6,7-Tetramethyl-2-[2-(dimethylamino)ethyl]-2,3-dihydrobenzofuran

N,N-dimethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl acetamide(3.1 g, 11.9 mmol) was dissolved in tetrahydrofuran (50 ml) and lithiumaluminum hydride (0.45 g) was added slowly under cooling. The reactionmixture was stirred for 30 minutes at room temperature and then pouredinto ice-cold water. The product was extracted with ethyl acetate. Theextract was washed with water, dried and concentrated. The residue waspurified by column chromatography on silica gel (chloroform-methanol,95:5) to obtain the desired compound (2.2 g, yield: 81.6%) as oil.

NMR (CDCl₃) δ1.42 (3H, s), 1.90 (2H, m), 2.06 (3H, s), 2.12 (3H, s),2.19 (3H, s), 2.23 (6H, s), 2.40 (2H, m), 2.82 (1H, d, J=15.4 Hz), 3.00(1H, d, J=15.4 Hz), 6.47 (1H, s).

Reference Example 732,4,6,7-Tetramethyl-2-(2-piperidinoethyl)-2,3-dihydrobenzofuran

The title compound was synthesized as oil according to the same manneras that described above (yield: 74.9%).

NMR (CDCl₃) δ1.42 (3H, s), 1.30-1.60 (6H, m), 1.90 (2H, m), 2.05 (3H,s), 2.12 (3H, s), 2.21 (3H, s), 2.40-2.60 (6H, m), 2.82 (1H, d, J=15.8Hz), 3.00 (1H, d, J=t5.8 Hz), 6.47 (1H, s).

Reference Example 744-(4-Chlorophenylimino)-3,5,6-trimethyl-2-(2-methyl-2-propenyl)-2,5-cyclohexadien-1-one

Titanium tetrachloride (2.42 ml, 22.1 mmol) was added dropwise to asolution of pyridine (7.13 ml, 88.2 mmol) in 1,2-dichloroethane (40 ml)and, after completion of addition, the reaction mixture was heated underreflux minutes in an argon atmosphere. After cooling of the reactionmixture, to the mixture was added a solution of3,5,6-trimethyl-2-(2-methyl-2-propenyl)-1,4-benzoquinone (3.00 g, 14.7mmol) and p-chloroaniline (5.62 g, 44.1 mmol) in 1,2-dichloroenhane (20ml) and the mixture was stirred 90° C. for 45 minutes in an argonatmosphere. The reaction mixture was cooled and filtered through Ceriteand the filtrate was washed with a saturated saline solution, dried andconcentrated. The residue was purified by silica gel columnchromatography (hexane-ethyl acetate, 93:7) to obtain the desiredcompound as oil (4.43 g, yield: 96.0%).

NMR δ1.53-2.20 (12H, m), 3.21 (2H, s), 4.51 (1H, s), 4.74 (1H, s), 6.68(2H, d, J=8.8 Hz), 7.30 (2H, d, J=8.8 Hz).

Reference Example 754-4-(Methoxyphenylimino)-3,5,6-trimethyl-2-(2-methyl-2-propenyl)-2,5-cyclohexadien-1-one

According to the same manner as that described in Reference Example 74,the titled compound as oil was obtained (yield: 19.1%).

NMR (CDCl₃) δ1.50-1.60 (3H, m), 1.77 (3H, broad s), 1.95-2.03 (3H, m),2.25 (3H, broad s), 3.16-3.25 (2H, m), 3.82 (3H, s), 4.46-4.58 (1H, m),4.74 (1H, broad s), 6.72 (214, d, J=9.0 Hz), 6.88 (2H, d, J=9.0 Hz).

Reference Example 764-(4-Chlorophenylamino)-3,5,6-trimethyl-2-(2-methyl-2-propenyl)phenol

To a solution of4-(4-chloropehnylimino)-3,5,6-trimethyl-2-(2-methyl-2-propenyl)-2,5-cyclonexadine-1-one(4.40 g, 14.0 mmol) in tetrahydrofuran (20 ml) was added a solution ofsodium hydrosulfite (24.4 g, 0.14 mol) in water (50 ml) and the mixturewas stirred at room temperature for 30 minutes. After separation of theorganic phase, the aqueous phase was extracted with ethyl acetate andthe extract was combined with the organic phase. The mixture was washedwith water and dried and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(hexane-ethyl acetate, 95:5) to obtain the desired compound as oil (4.30g, yield: 97.2%).

NMR (CDCl₃) δ1.80 (3H, s), 2.11 (3H, s), 2.12 (3H, s), 2.19 (3H, s),3.40 (2H, s), 4.68 (1H, s), 4.87 (1H, s), 5.04 (1H, s), 5.14 (1H, broads), 6.34 (2H, d, J=8.8 Hz), 7.06 (2H, d, J=8.8 Hz).

Reference Example 774-(4-Metnoxyphenylamino)-3,5,6-trimethyl-2-(2-methyl-2-propenyl)phenol

According to the same manner as that described in Reference Example 74,the titled compound as oil was obtained <yield: 98.2%).

NMR (CDCl₃) δ1.80 (3H, s), 2.14 (6H, s), 2,19 (3H, s), 3.40 (2H, s),3.73 (3H, s), 4.69 (1H, s), 4.85-5.05 (3H, m), 6.38 (2a, d, J=8.8 Hz),6.73 (2H, d, J=8.8 Hz).

Reference Example 783,5,6-Trimethyl-2-(2-methyl-2-propenyl)-4-phenyl-aminophenol

Titanium tetrachloride (2.58 ml, 23.4 mmol) was added dropwise to asolution of pyridine (7.60 ml, 93.6 mmol) in 1,2-dichloroethane (40 ml)and, after completion of the addition, the reaction mixture was heatedunder reflux for 30 minutes in an argon atmosphere. After cooling of thereaction mixture, a solution of3,5,6-trimethyl-2-(2-methyl-2-propenyl)-1,4-benzoquinone (2.40 g, 11.7mmol) and aniline (3.35 ml, 35.1 mmol) in 1,2-dichloroethane (5 ml) wasadded thereto and the mixture was stirred at 90° C. for 2 hours in anargon atmosphere. The reaction mixture was cooled and filtered throughCerite and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane-ethylacetate, 98:2). The resulting compound was dissolved in tetrahydrofuran(10 ml) and to the solution was added a solution of sodium hydrosulfite(12 g, 69 mmol) in water (30 ml). The mixture was stirred at roomtemperature for 30 minutes. The organic phase was separated and theaqueous phase was extracted with ethyl acetate. The extract was combinedwith the organic phase and the mixture was washed with water and driedand the solvent was distilled oil under reduced pressure. The residuewas purified by silica gel chromatography (hexaneethyl acetate, 95:5) toobtain the desired compound as oil (1.41 g, yield: 42.8%).

NMR (CDCl₃) δ1.80 (3H, s), 2.14 (6H, s), 2.19 (3H, s), 3.41 (2H, s),4.69 (1H, s), 4.87 (1H, s), 5.03 (1H, s), 5.11 (1H, broad s), 6.42 (2H,d, J=7.4 Hz), 6.68 (1H, t, J=7.4 Hz), 7.13 (2H, t, J=7.4 Hz).

Experiment 1

Effect of drugs on the change of the behavior induced by spinalintrathecal injection of FeCl₂ in mice

Male Slc: ICR mice (5 weeks) (10 mice per group) were used. Saline (5μl/mouse) containing 50 mM FeCl₂ was injected into the subarachnoidspace between the 6th lumbar segment and the 1st sacral and scored asfollows.

Score Behavioral responses

0: normal

1: vigorously biting lower extremity or lower abdomen

2: a) extremely biting lower body with rolling b) hyperreactive andaggressive to external stmuli c) tremor

at least one of above three behavioral changes are observed

3: clonic convulsion

4: tonic convulsion or paralysis of one of both extremities

5: death

Percent inhibitions were calculated based on the scores evaluated above.The test compounds were orally administered 30 minutes prior to ferrouschloride injection.

Table 1 shows the mean scores and their percent inhibitions obtained byoral administration of 100 mg/kg of the compound (I).

                  TABLE 1                                                         ______________________________________                                                       Mean Score                                                     Test           Administration of                                              Compound  Test Compound of        %                                           Ex. No.   100 mg/kg       Saline  inhibition                                  ______________________________________                                        103       0.1             4.9     98.0                                         1        1.2             4.6     73.9                                        84        0.5             4.6     89.1                                        47        1.0             4.9     79.6                                        85        0.6             4.6     87.0                                        ______________________________________                                    

The above results clearly show that the compounds of the presentinvention have superior depressant activity of central nervous systemdisorders caused by formation of lipoperoxide due to ferrous chloride.

As described hereinabove, the compounds (I) of the present inventionhave lipoperoxide formation inhibitory (antioxidation) activity, andlipoxygenase and HHT formation inhibitory or suppression activity, andare useful as medicines for preventing and treating circulatory,inflammatory and allergic diseases.

What is claimed is:
 1. A d- or l-isomer of5-amino-2-bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzo[b]furan.
 2. Acompound which is5-amino-2-bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzo[b]furan.